In a paper published today in Nature, Bear and colleagues have now shown that tuberous sclerosis, another rare disease characterized by autism and mental retardation, is caused by the opposite malfunction — too little synthesis of those synaptic proteins.

Though the findings might seem counterintuitive, they fit into the theory that autism can be caused by a wide range of brain-synapse glitches, Bear says. “The general concept is that appropriate brain function occurs within a very narrow physiological range that is tightly maintained,” he says. “If you exceed that range in either direction, you have an impairment that can manifest as this constellation of symptoms, which very frequently go together — autism spectrum disorder, intellectual disability and epilepsy.”

Furthermore, the study suggests that any potential drugs developed to treat the cellular origins of autism would need to be carefully matched to the patient to ensure they do more good than harm. Drugs developed to treat Fragile X syndrome have shown encouraging results in human studies and are currently in Phase III clinical trials.

Making connections
Bear, the Picower Professor of Neuroscience and a member of MIT’s Picower Institute for Learning and Memory, did not set out to study autism or Fragile X syndrome, but ended up discovering how Fragile X develops through his studies of a receptor found on the surface of neurons.

That receptor, known as mGluR5, plays an important role in transmitting signals between two neurons at a synapse (known as the presynaptic and postsynaptic neurons). When the presynaptic cell releases a neurotransmitter called glutamate, it binds to mGluR5 on the postsynaptic neuron, triggering synthesis of new synaptic proteins. Fragile X protein (FMRP) acts as a brake on this protein synthesis. “The appropriate level of protein synthesis is generated by a balance between stimulation by mGluR5 and repression by FMRP,” Bear says.

When FMRP is lost, there is too much protein synthesis, which leads to the symptoms seen in Fragile X syndrome: learning disabilities, autistic behavior and seizures. Bear and others have since shown that blocking mGluR5 in mice can reverse those symptoms.

After making the connection between Fragile X and mGluR5, Bear and his colleagues started to wonder if mGluR5 overactivity might also cause other single-gene syndromes that produce autism symptoms. They began their investigation with tuberous sclerosis (TSC).

The researchers, including co-authors Benjamin Auerbach, a graduate student in brain and cognitive sciences, and research scientist Emily Osterweil, felt confident in their hypothesis that they would see a similar synaptic defect in TSC as they had seen in Fragile X. In fact, when they submitted their application for funding for the study, “our reviewers thought we were being too conservative, because it seemed to them that the answer was so obvious, it was hardly worth doing the experiment,” Bear recalls.

However, the team found the exact opposite of what they and the reviewers had expected. The two diseases “appear to be mirror images of each other,” Bear says. In mice with TSC, synapses have too little protein synthesis — so instead of improving when treated with a drug that inhibits mGluR5, the animals respond to a drug that stimulates it.

Tailored treatments
The findings show that not all cases of autism spectrum disorder will respond to the same kind of treatment, Bear says. “This study identified one functional axis, and it will be important to know where a patient lies on this axis to devise the therapy that will be effective,” he says. “If you have a disorder of too little protein synthesis, you don’t want to inhibit the neurotransmitter receptor that stimulates protein synthesis, and vice versa.”

This should not be surprising, he says, pointing out that psychiatric-drug development has encountered the same difficulties because disorders such as bipolar disorder and schizophrenia have such varied origins. In the case of autism, researchers hope that identifying the root causes of single-gene disorders can help them figure out how to treat other forms of autism that may have similar origins.

“We have a huge advantage of really getting down to what actually is wrong in the brain in these diseases,” Bear says. “Of course what we’d like to do is be able to go from these rare known causes of autism, which may account for at most 10 percent of cases of autism, into idiopathic autism — autism of unknown cause — and try to have some hope of selecting the right therapy for those individuals.”

There are currently no good tests for which genetic markers a particular autistic patient may have, but if drugs that inhibit and/or stimulate mGluR5 are approved, scientists may be able to identify which autistic patients respond to which drugs, and then try to identify a biomarker in those patients that could be used for future diagnostic tests.

Bear and his colleagues are now studying other single-gene disorders, including Angelman syndrome and Rett syndrome, to see if they also affect mGluR5 activity. They are also trying to figure out, in more detail, the steps in the mGluR5/protein-synthesis pathway.

Material adapted from MIT.

Reference / Abstract
Benjamin D. Auerbach, Emily K. Osterweil, & Mark F. Bear (2011). Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480, 63–68.

Abnormalities included changes in the composition of cells in the cortex, the largest brain structure in humans, and of neurons that secrete two key chemical messengers. Neurons that make long-distance connections between the brain’s hemispheres tended to be in short supply.

Most patients with Timothy Syndrome meet diagnostic criteria for an autism spectrum disorder. Yet, unlike most cases of autism, Timothy syndrome is known to be caused by a single genetic mutation.

Representative iPSC-derived neurons from Timothy Syndrome patient (bottom) shows increased numbers of neurons that produce the chemical messengers norepinephrine and dopamine, compared to those from a control subject (top). Source: Ricardo Dolmetsch, Ph.D., Stanford University

Dolmetsch, and colleagues, report on their findings Nov. 27, 2011 in the journal Nature Medicine.

“Unlike animal research, the cutting-edge technology employed in this study makes it possible to pinpoint molecular defects in a patient’s own brain cells,” said NIMH Director Thomas R. Insel, M.D. “It also offers a way to screen more rapidly for medications that act on the disordered process.”

Prior to the current study, researchers knew that Timothy syndrome is caused by a tiny glitch in the gene that codes for a calcium channel protein in cell membranes. The mutation results in too much calcium entering cells, causing a tell-tale set of abnormalities throughout the body. Proper functioning of the calcium channel is known to be particularly critical for proper heart rhythm – many patients die in childhood of arrhythmias – but its role in brain cells was less well understood.

To learn more, Dolmetsch and colleagues used a new technology called induced pluripotent stem cells (iPSCs). They first converted skin cells from Timothy Syndrome patients into stem cells and then coaxed these to differentiate into neurons.

“Remarkable reproducibility” observed across multiple iPSC lines and individuals confirmed that the technique can reveal defects in neuronal differentiation – such as whether cells assume the correct identity as the brain gets wired-up in early development, said the researchers. Compared to those from controls, fewer neurons from Timothy Syndrome patients became neurons of the lower layers of the cortex and more became upper layer neurons. The lower layer cells that remained were more likely to be the kind that project to areas below the cortex. In contrast, there were fewer-than-normal neurons equipped to form a structure, called the corpus callosum, which makes possible communications between the left and right hemispheres.

Many of these defects were also seen in parallel studies of mice with the same genetic mutation found in Timothy syndrome patients. This supports the link between the mutation and the developmental abnormalities.

Several genes previously implicated in autism were among hundreds found to be expressed abnormally in Timothy Syndrome neurons. Excess cellular calcium levels also caused an overproduction of neurons that make key chemical messengers. Timothy Syndrome neurons secreted 3.5 times more norepinephrine and 2.3 times more dopamine than control neurons. Addition of a drug that blocks the calcium channel reversed the abnormalities in cultured neurons, reducing the proportion of catecholamine-secreting cells by 68 percent.

The findings in Timothy Syndrome patient iPSCs follow those in Rett Syndrome, another single gene disorder that often includes autism-like symptoms. About a year ago, Alysson Muotri, Ph.D., and colleagues at University of California, San Diego, reported deficitsin the protrusions of neurons, called spines, that help form connections, or synapses. The Dolmetsch team’s discovery of earlier (neuronal fate) and later (altered connectivity) defects suggest that disorders on the autism spectrum affect multiple stages in early brain development.

“Most of these abnormalities are consistent with other emerging evidence that ASDs arise from defects in connectivity between cortex areas and show decreased size of the corpus callosum,” said Dolmetsch. “Our study reveals how these might be traceable to specific mechanisms set in motion by poor regulation of cellular calcium. It also demonstrates that neurons derived from iPSCs can be used to identify the cellular basis of a neurodevelopmental disorder.”

Forebrain of a mouse genetically engineered to express the mutated gene that causes Timothy Syndrome (TS) shows fewer neurons contributing to a brain structure responsible for long-distance communications between the left and right hemispheres, called the corpus callosum, compared to the same structure in a control animal (Ctrl). Human iPSCs from TS patients showed a similar reduction. Source: Ricardo Dolmetsch, Ph.D., Stanford University

The mechanisms identified in this study may become potential targets for developing new therapies for Timothy Syndrome and may also provide insights into the neural basis of deficits in other forms of autism, said Dolmetsch.

Material adapted from NIMH.

Reference
Using iPS cell-derived neurons to uncover cellular phenotypes associated with Timothy Syndrome. Pasca SP, Portmann T, Voineagu I, Yazawa M, Shcheglovitov O, Pasca AM, Cord B, Palmer TD, Chikahisa S, Seiji N, Bernstein JA, Hallmayer J, Geschwind DH, Dolmetsch RE. November 27, 2011. Nature Medicine.

The relative risk of autism spectrum disorder in children of mothers on valproate monotherapy was found to be 2.6 times that of children not exposed to antiepileptic medication in utero. The risk of childhood autism was almost five-fold increased compared to children without prenatal exposure to valproate.

Dr. Christensen cautions that while there appears to be a relationship between valproate and autism, women of childbearing age should not stop taking the medication without consulting their doctors.

“Stopping any anticonvulsant medication poses a serious danger,” Dr. Christensen says. “Women taking valproate who are contemplating pregnancy should consult with their doctors about the possibility of transitioning to another drug, or reducing the dosage of their present medication when that isn’t possible.”

To arrive at their estimates, Christensen and his team searched data from several national registries. They identified children born between 1996 and 2006 and mothers with epilepsy who were taking valproate 30 days prior to the day of conception to the day of birth. The researchers then identified the children born during this period who were diagnosed with autism spectrum disorder and specifically assessed the subgroup diagnosed with childhood autism.

Material adapted from American Epilepsy Society (AES).

Photosensitivity in children with epilepsy alone is reported to range from 2 – 14%. A pilot study to determine the incidence of photosensitivity in children with ASD has found a significant and unexpected higher rate of nearly 30% photosensitivity in adolescents with epilepsy and autism comorbidity. (Abstract 3.109) The study, presented at the American Epilepsy Society’s 65th annual meeting, is the first report of this marked difference in response to intermittent photic stimulation.

Investigators at Children’s Hospital Boston reviewed the records of children diagnosed with ASD between December 2010 and May 2011. Those given an EEG prior to or during the search period were included in the study. The EEG reports were examined to determine the presence or absence of a photoparoxysmal response (PPR) to intermittent photic stimulation.

“Our study found a high overall incidence of photosensitivity in 25 percent of children over 15 years of age with autism spectrum disorder, and an even higher rate of 29.4 percent in that age group of children who had both epilepsy and autism,” says lead author Jill Miller-Horn. “This finding has not been previously reported.”

Dr. Miller-Horn noted the relatively small size of the study. “Larger scale prospective studies are needed to confirm this trend,” she said. “Further study is also needed to identify the importance of these findings in the pathophysiology of epilepsy in children with autism spectrum disorder.”

Material adapted from American Epilepsy Society (AES).

More than 75% of the children screened positive for developmental delay, 41% of them with autism. Although many of the cases had been previously diagnosed, more than one-third of the children did not have a prior DD or autism diagnosis and were referred for further confirmatory evaluation.

According to Anne Berg and Breanne Fisher of the investigative team, “The yield of screening in the EMU setting for developmental and behavioral comorbidities is sufficiently high to support routine screening of both new onset and established cases of pediatric epilepsy. Our findings also suggest that all children seen in the epilepsy clinic should be screened for these comorbidities.”

The study was conducted among children under age five seen between November 1, 2010 and May 15, 2011. Parents were asked to complete the developmental screening instrument (Ages and Stages Questionnaire, ASQ) and one of two autism screening instruments used in the study. No child screened positive for autism alone.

The investigators have now focused the program on evaluating the prospective use of a more extensive battery of screening tools with new-onset patients followed over time.

Material adapted from American Epilepsy Society (AES).

Research Director David Amaral and Assistant Professor Christine Wu Nordahl

The study was led by Christine Wu Nordahl, a researcher at the UC Davis MIND Institute and an assistant professor in the Department of Psychiatry and Behavioral Sciences and David G. Amaral, Beneto Foundation Chair, MIND Institute Research Director and University of California Distinguished Professor in the Department of Psychiatry and Behavioral Sciences.

“The finding that boys with regressive autism show a different form of neuropathology than boys with early onset autism is novel,” Nordahl said. “Moreover, when we evaluated girls with autism separately from boys, we found that no girls – regardless of whether they had early onset or regressive autism – had abnormal brain growth.”

Brain enlargement has been observed in previous studies of autism. However, prior to this study, little was known about how many and which children with autism have abnormally large brains.

“This adds to the growing evidence that there are multiple biological subtypes of autism, with different neurobiological underpinnings,” Amaral said.

Autism is a neurodevelopmental disorder whose symptoms include deficits in language and social interaction and communication. The condition affects 1 in 110 children born today, according to the U.S. Centers for Disease Control and Prevention. It is diagnosed more frequently in male children than female children – at a ratio of 4 to 1.

The current study is one of the first published from data collected by the UC Davis MIND Institute Autism Phenome Project (APP). The project’s goal is to recruit and enroll as many very young children as possible in order to collect sufficient biological and behavioral information to characterize different autism subgroups and to explore different neural, immunologic, and genetic signatures of autism.

For the study, the authors enrolled a total of 180 children between age 2 and 4. One hundred and fourteen of the participants had autism spectrum disorder; the remaining participants were 66 age-matched typically developing controls. Of the children with autism, 54 percent were diagnosed with the regressive form and 46 with the non-regressive type.

The researchers collected magnetic resonance imaging (MRI) scans on 180 participants at age 3. To evaluate the rate of brain growth prior to age 3, they analyzed head circumference measurements taken from pediatric well-baby visits from birth through 18 months. Roughly half of the children with autism were reported by their parents as having experienced a regression, characterized by the loss of previously acquired language and social skills.

The MRIs were carried out on study participants during natural, nighttime sleep using protocols developed specifically for the Autism Phenome Project by Nordahl.

“Obtaining MRI scans in 3-year-old children without the use of sedation may seem quite challenging. But, by working closely with the parents, we actually were successful more than 85 percent of the time. Patience on the part of everyone and the dedication of the families was critical for our success,” Nordahl said.

The study found that accelerated head growth and brain enlargement was consistently observed only in the subset of children diagnosed with regressive autism. Specifically, total brain volume in 3-year-old males with regressive autism was more than 6 percent larger than that of age-matched typically developing peers. Twenty-two percent of boys with regressive autism, as opposed to 5 percent of boys without regressive autism, had enlarged brains, the study found.

Changes in brain size were not apparent in boys who did not experience a regression. Girls with autism, regardless of autism onset status, also did not show abnormal brain growth. The study findings suggest that abnormalities in overall brain growth are specific to male children with the regressive type of autism, and that rapid brain growth may be a risk factor for regression, the researchers said.

While brain size was clearly larger at age 3, the study also determined when the precocious growth began, by examining records of head circumference that provides a reasonable estimate of brain size in young children. These analyses clearly indicated that brain growth diverged from normal at around 4 to 6 months of age. This is of particular interest, because many families believe that the trigger that led to their child’s regression took place close to the time that the regression happened. But the data reported in this paper indicate that the process leading to the enlarged brain, which presumably also is associated with the onset of autism, started when the child was a newborn.

Much remains to be elucidated regarding brain changes associated with autism, the authors note. In the current study, not all boys with regression demonstrate the precocious brain growth. The investigative team also continues efforts to define the underlying brain pathology in children with early onset autism and in girls with autism.

“It is not clear how many different types of autism will be identified,” Amaral said. “The purpose of defining different types of autism is to more effectively study the cause of each type and eventually determine effective preventative measures and better, individualized treatments. This is a first step in defining autism subtypes based on the data from the Autism Phenome Project, but it certainly will not be the last. There are already indications that other subtypes of autism will be more closely associated with immunological differences or genetic alterations.”

The study’s other authors are Nicholas Lange of the Department of Psychiatry and Biostatistics at Harvard University Schools of Medicine and Public Health McLean Hospital; Deana D. Li, Lou Ann Barnett, Aaron Lee, Tony J. Simon, Sally Rogers and Sally Ozonoff of the UC Davis MIND Institute and the Department of Psychiatry and Behavioral Sciences in the UC Davis School of Medicine; and Michael H. Buonocore of the Department of Radiology, UC Davis School of Medicine.

Material adapted from UC Davis Health System.

Brain and head overgrowth in children with autism and neural dysfunction are evident at young ages in multiple brain regions, including the prefrontal cortex (PFC), that are involved in higher-order social, emotional, communication, and cognitive development.

“Therefore, knowledge of the neural basis of overgrowth could point to early causal mechanisms in autism and elucidate the neural functional defects that engender autistic symptoms. In the first magnetic resonance imaging (MRI) report of early brain overgrowth in autism a decade ago, it was theorized that excess numbers of neurons could be an underlying cause, perhaps due to prenatal dysregulation of proliferation, apoptosis [cell death], or both. However, the neural basis of early overgrowth remains unknown and can only be known from direct quantitative studies of the young postmortem autistic brain,” according to background information in the article.

The researchers examined whether early brain overgrowth in children with autism involves excess neuron numbers in the PFC. The study included postmortem prefrontal tissue from 7 autistic and 6 control male children, ages 2 to 16 years, which was examined by expert anatomists who were blinded to diagnostic status. Number and size of neurons were quantified within the dorsolateral (DL-PFC) and mesial (M-PFC) subdivisions of the PFC. Cases were from the eastern and southeastern United States and died between 2000 and 2006.

The researchers found statistically significant differences in neuron counts in the PFC in the autistic children compared with controls. There were 79 percent more neurons in DL-PFC in the autistic cases compared with the control cases and 29 percent more in M-PFC. The average DL-PFC count in the autistic children was 1.57 billion neurons compared with an average of 0.88 billion neurons in control children. The average M-PFC count in the autistic group was 0.36 billion neurons compared with an average of 0.28 billion neurons in controls. “Together, these 2 subdivisions gave a total combined prefrontal neuron count that was 67 percent greater in the autistic children compared with controls,” the authors write.

The researchers also found that the brain weight in the autistic sample deviated from normative average weight for age by 17.6 percent, while control brains deviated from age-based norms by 0.2 percent.

“Our sample of autistic children was not large enough to statistically examine brain-behavior relationships. Future studies with many more cases of autistic children might reveal important relationships between neuron counts and symptom severity or intellectual ability,” the authors write.

“To our knowledge, this study is the first direct quantitative test and confirmation of the theory that a pathological overabundance of neurons in critical brain regions is present at a young age in autism. Because cortical neurons are generated in prenatal, not postnatal life, pathological overabundance of neurons indicates early developmental disturbances in molecular and genetic mechanisms that govern proliferation, cell cycle regulation, and apoptosis. Therefore, the finding has significance for understanding the etiological and neural development and functional origins of autism.”

Material adapted from JAMA.

Reference
JAMA. 2011;306[18]:2001-2010.

In the field of autism spectrum disorders (ASDs), diagnostic instruments have been helpful in defining populations, merging samples, and comparing results across studies, according to background information in the article. Nevertheless, best-estimate clinical (BEC) diagnoses of specific autism spectrum disorders have long been the gold standard. These specific ASDs include autistic disorder, pervasive developmental disorder-not otherwise specified (PDD-NOS), and Asperger’s syndrome.

Researchers conducted an observational study to determine whether the relationships between behavioral appearance and clinical diagnoses of different ASDs vary across 12 university-based sites. The study included 2,102 participants (1,814 male) between 4 and 18 years of age who met autism spectrum criteria on two diagnostic assessments and who had a clinical diagnosis of an ASD. The study authors collected demographic, diagnostic, and developmental data for genetic research.

The authors report that clinical distinctions among categorical diagnostic ASD subtypes were not reliable, even across sites with well-documented fidelity using standardized diagnostic instruments.

“Although distributions of scores on standardized measures were similar across sites, significant site differences emerged in best-estimate clinical diagnoses of specific autism spectrum disorders,” the authors write. “Relationships between clinical diagnoses and standardized scores, particularly verbal IQ, language level, and core diagnostic features, varied across sites in weighting of information and cutoffs,” they continue.

The authors suggest that differences in diagnoses could reflect regional variations. “For example, in some regions, children with diagnoses of autistic disorder receive different services than do children with other ASD diagnoses; elsewhere, autistic disorder diagnoses may be avoided as more stigmatizing than diagnoses of PDD-NOS or Asperger syndrome,” they write.

The authors point out that their study results have implications for revisions of current diagnostic frameworks.

“Results support the move from existing subgroupings of autism spectrum disorders to dimensional descriptions of core features of social affect and fixated, repetitive behaviors, together with characteristics such as language level and cognitive function,” they conclude.

Material adapted from JAMA.

Reference
Arch Gen Psychiatry. Published online November 7, 2011. doi:10.1001/archgenpsychiatry.2011.148.

Autism spectrum disorders are a group of complex illnesses with different causes and origins. Neuronal dysfunction in the cerebral cortex and other regions of the brain could contribute to the cognitive and behavioral defects in autism, according to background information in the article. Neurons are nerve cells that send and receive electrical signals within the body.

Researchers examined the postmortem brain tissue of 16 individuals diagnosed with autism spectrum disorder (average age 17.4 years; range 2 to 60 years) and 16 controls without autism (ranging in age from less than one year to 70 years). The tissue was obtained through the Autism Tissue Program.

The study searched, on a genome-wide scale, for genes that show an abnormal epigenetic signature – specifically histone methylation. Histones are small proteins attached to the DNA that control gene expression and activity. While genetic information is encoded by the (genome’s) DNA sequence, methylation and other types of histone modifications regulate genome organization and gene expression.

The study found hundreds of loci (the places genes occupy on chromosomes) across the genome affected by altered histone methylation in the brains of autistic individuals. However, only a small percentage – less than 10 percent – of the affected genes were affected by DNA mutations. It remains to be determined whether or not genetic changes elsewhere in the genome contributed to the observed epigenetic changes, or whether non-genetic factors were responsible for the disease process in some of the affected individuals.

“Prefrontal cortex neurons from subjects with autism show changes in chromatin (the substance of chromosomes) structures at hundreds of loci genome-wide, revealing considerable overlap between genetic and epigenetic risk maps of developmental brain disorders,” the authors conclude.

Material adapted from JAMA.

Reference
Arch Gen Psychiatry. Published online November 7, 2011. doi:10.1001/archgenpsychiatry.2011.151.

Researcher Laurent Mottron

“Recent data and my own personal experience suggest it’s time to start thinking of autism as an advantage in some spheres, not a cross to bear,” Mottron said.

Mottron’s research team has strongly established and replicated the abilities and sometimes superiorities of those with autism in multiple cognitive operations such as perception and reasoning, as have others. His group includes several autistic persons, and one of them, Michelle Dawson, is a particular success. Dawson makes major contributions to our understanding of the condition through her work and her judgment.

“Michelle challenged my scientific perception of autism,” Mottron explained. Dawson’s insight is the interpretation of autistic strengths as the manifestation of authentic intelligence rather than a kind of trick of the brain that allows them to mindlessly perform intelligent tasks. “It’s amazing to me that for decades scientists have estimated the magnitude of mental retardation based on the administration of inappropriate tests, and on the misinterpretation of autistic strengths,” Mottron added.

“We coined a word for that: normocentrism, meaning the preconception you have that if you do or are something, it is normal, and if autistic do or have it, it is abnormal,” Mottron said. He points out that there is a strong motivation for this perception, as it is the standard rhetoric of fund raising and grant applications, but that it comes at a cost in terms of how autistic people are designated in social discourse.

“While state and nonprofit funding is important for advancing our understanding of the condition, it’s exceptional that these tools are used to work towards goals identified by the autistic community itself,” Mottron said, lamenting the fact that many autistic persons end up working repetitive, menial jobs, despite their intelligence and aptitude to make much more significant contributions to society.

“Dawson and other autistic individuals have convinced me that, in many instances, people with autism need more than anything opportunities, frequently support, but rarely treatment,” Mottron said. “As a result, my lab and others believe autism should be described and investigated as an accepted variant within human species, not as a defect to be suppressed.”

Laurent Mottron’s article claims that science should do its part to bring back autistic people as members of the human community. His paper goes into more detail about the specific abilities of some autistic individuals, provides a range of real world examples, and offers some personal insights into his collaborations with Michelle Dawson.

Material adapted from Université de Montreal.

Reporting in the current online edition of the journal Human Brain Mapping, senior author Jennifer G. Levitt, a professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA; first author Xua Hua, a UCLA postdoctoral researcher; and colleagues found aberrant growth rates in areas of the brain implicated in the social impairment, communication deficits and repetitive behaviors that characterize autism.

Autism is thought to affect one in 110 children in the U.S., and many experts believe the numbers are growing. Despite its prevalence, little is known about the disorder, and no cure has been discovered.

Normally, as children grow into teenagers, the brain undergoes major changes. This highly dynamic process depends on the creation of new connections, called white matter, and the elimination, or “pruning,” of unused brain cells, called gray matter. As a result, our brains work out the ideal and most efficient ways to understand and respond to the world around us.
Although most children with autism are diagnosed before they are 3 years old, this new study suggests that delays in brain development continue into adolescence.

“Because the brain of a child with autism develops more slowly during this critical period of life, these children may have an especially difficult time struggling to establish personal identity, develop social interactions, and refine emotional skills,” Hua said. “This new knowledge may help to explain some of the symptoms of autism and could improve future treatment options.”

The researchers used a type of brain-imaging scan called a T1-weighted MRI, which can map structural changes during brain development. To study how the brains of boys with autism changed over time, they scanned 13 boys diagnosed with autism and a control group of seven non-autistic boys on two separate occasions. The boys ranged in age from 6 to 14 at the time of the first scan; on average, they were scanned again approximately three years later. By scanning the boys twice, the scientists were able to create a detailed picture of how the brain changes during this critical period of development.

For the first time, UCLA researchers have shown that the connections between brain regions that are important for language and social skills grow much more slowly in boys with autism than in non-autistic children.

Besides seeing that the white-matter connections between those brain regions that are important for language and social skills were growing much slower in the boys with autism, they found a second anomaly: In two areas of the brain — the putamen, which is involved in learning, and the anterior cingulate, which helps regulate both cognitive and emotional processing — unused cells were not properly pruned away.

“Together, this creates unusual brain circuits with cells that are overly connected to their close neighbors and under-connected to important cells further away making it difficult for the brain to process information in a normal way,” Hua said. “The brain regions where growth rates were found to be the most altered were associated with the problems autistic children most often struggle with — social impairment, communication deficits and repetitive behavior,” she added.

Future studies using alternative neuroscience techniques should attempt to identify the source of this white-matter impairment, the researchers said.

“This study provides a new understanding of how the brains of children with autism are growing and developing in a unique way,” Levitt said. “Brain imaging could be used to determine if treatments are successful at addressing the biological difference. The delayed brain growth in autism may also suggest a different approach for educational intervention in adolescent and adult patients, since we now know their brains are wired differently to perceive information.”

Other authors on the study included Paul M. Thompson, Alex D. Leow, Sarah K. Madsen, Rochelle Caplan, Jeffry R. Alger, Joseph O’Neill, Kishori Joshi, Susan L. Smalley and Arthur W. Toga, all of UCLA. Support was provided by the National Institutes of Health, the National Alliance for Autism Research, the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke. The authors report no conflict of interest.

Material adapted from University of California, Los Angeles (UCLA), Health Sciences.

“Association of a MET genetic variant with autism-associated maternal autoantibodies to fetal brain proteins and cytokine expression,” is published online today in the journal Translational Psychiatry, a Nature publication.

“Our study gives strong support for the idea that, in at least some cases, autism results from maternal immunity gone overboard,” said Judy Van de Water, a professor of internal medicine and a researcher affiliated with the UC Davis MIND Institute. “This is the first time that a genetic factor known to be important in autism and its effects have been demonstrated.”

Autism is a neurodevelopmental disorder that affects a child’s ability to learn and communicate socially. It affects an estimated 1 in 110 children in the United States, according to the U.S. Centers for Disease Control and Prevention.

For the study, Van de Water and her colleagues examined the action of the MET gene, which has a known association with autism, among 200 mothers of children with autism and 150 mothers of typically developing children enrolled in the Northern California-based Childhood Autism Risks from Genetics and the Environment (CHARGE) Study. All of the study participants were between 24 and 60 months of age at the time of study enrollment, lived with one biological parent, and spoke either English or Spanish.

The researchers found that the C-allele of the MET gene is more common in mothers with several immunologic abnormalities that might contribute to the development of autism. Analysis of the MET C-allele is a method of determining susceptibility for immune dysregulation in the mothers.

One abnormality they attributed to the MET C allele is the presence of antibodies against fetal brain proteins in the blood of the mothers. These brain-attacking antibodies occur in some mothers with an autistic child, but are not found in mothers of typically developing children. It is believed that these antibodies somehow injure the developing brain of the fetus, and in some instances may cause autism.

Researchers do not yet know when or how the antibodies are formed, or precisely what happens to the brain tissue exposed to them, but based on a collaborative paper with Loren Martin at Azuza Pacific University, they appear to have pathologic significance, or a functional effect on brain development, changing the way the brain develops. Van de Water and her group are still working on the precise effect of these maternal antibodies on the developing brain.

The investigators also found that MET protein levels are reduced in cells from mothers with one C allele and one normal allele, and were even lower in those with two C alleles. Lower MET protein on the cell surface may increase susceptibility to a more intense and prolonged immune response when the cells are activated, like exposure to a bacteria or virus. This, in turn, could make these individuals more prone to forming antibodies against ‘self’ proteins, such as those found in the fetal brain.

In addition, the investigators evaluated the functional polymorphism in the study participants’ immunological cytokines, molecules that tell other cells what to do. The cytokine IL-10, an important anti-inflammatory marker, was reduced in women with the MET C allele. IL-10 is a well-studied immunosuppressive molecule that is important for preventing autoimmunity. A reduction in IL-10 would increase the chances that an inflammatory response would continue unchecked.

“The convergence of these two distinct associations with autism risk — that of maternal antibodies to fetal brain proteins and the MET C allele — provides the first link between an autism susceptibility gene and its effects,” Van de Water said.

Daniel B. Campbell, assistant professor of psychiatry and the behavioral sciences at the Zilkha Neurogenetic Institute of the University of Southern California, is co-principal investigator of the study.

“The presence of maternal antibodies to fetal blood proteins is one of the best markers known for autism, accounting for about 12 percent of cases. In contrast, genetic factors previously identified in children with autism account for only 2 or 3 percent of cases,” Campbell said.

“Now we not only have a marker, but we are starting to understand the actual mechanisms of what causes autism,” Campbell said. “These findings can greatly enhance our understanding of the origins of some cases of autism and may directly lead to screening tests and treatments to prevent it.”

Why women with the C allele form antibodies against fetal brain proteins is another important area of interest, according to Van de Water, because it suggests a hyper-responsive immune system. Proteins associated with the MET gene function as key blockers of immune activity.

“Our study has found that a kind of safety switch that regulates the immune system and prevents it from targeting the brain of the developing fetus is defective in some mothers of children who later develop autism,” Van de Water said.

Van de Water said the relationship between autism and aberrations in the immune system, once a radical notion in the scientific community, is now becoming a well-accepted and very fruitful focus of research.

“While it is not known how the antibody response against fetal brain proteins arise, it may be possible to one day treat susceptible women to reduce the likelihood of having an autistic child,” Van de Water said.

Other study authors include Paul Ashwood, Luke Heuer, and Daniel Braunschweig, all of UC Davis.

Material adapted from University of California – Davis Health System.

Researcher Michael Stern

“It appears that both Type 2 diabetes and autism have a common underlying mechanism – impaired glucose tolerance and hyperinsulinemia,” said Rice University biochemist Michael Stern, author of the opinion paper, which appears online in this month’s issue of Frontiers in Cellular Endocrinology.

Hyperinsulinemia, often a precursor to insulin resistance, is a condition characterized by excess levels of insulin in the bloodstream. Insulin resistance is often associated with both obesity and Type 2 diabetes.

“It will be very easy for clinicians to test my hypothesis,” said Stern, professor of biochemistry and cell biology at Rice. “They could do this by putting autistic children on low-carbohydrate diets that minimize insulin secretion and see if their symptoms improve.”

Stern said the new finding also suggests that glucose tolerance in pregnant women may need to be addressed more seriously than it is now. Stern said he first realized there could be a common link between Type 2 diabetes and autism a few years ago, but he assumed someone else had already thought of the idea.

Stern’s lab, which is located at Rice’s BioScience Research Collaborative, specializes in investigating the genetic interactions associated with genetic diseases like neurofibromatosis, a disorder in which patients are several times more likely to be afflicted with autism and autism spectrum disorders (ASD) like Asperger’s syndrome.

Autism and ASD are neurological disorders that have a strong but poorly understood genetic basis. The U.S. Centers for Disease Control and Prevention estimates that about nine out of 1,000 U.S. children are diagnosed with ASD.

Stern said at least four genes associated with increased frequency in autism are known to produce proteins that play key roles in a biochemical pathway known as PI3K/Tor. Stern said he had been studying a form of abnormal function in the synapses of fruit flies that was remarkably similar to abnormalities observed in rats and mice with defects in a different pathway known as mGluR-mediated long-term depression.

“I had also spent a lot of time thinking about insulin signaling because another project in my lab is an endocrinology project in which we’re studying how key proteins involved in insulin signaling affect the timing of metamorphosis in fruit flies,” Stern said.

From his studies in both areas, Stern knew two things: PI3K/Tor was the major pathway for insulin signals within cells, and insulin could affect synapses in a remarkably similar way to the mGluR defects associated with autism.

“When I read that the incidence of autism was increasing, and combined that with the fact that the incidence of Type 2 diabetes is also increasing, it seemed reasonable that each increase could have the same ultimate cause — the increase in hyperinsulinemia in the general population,” Stern said. “I didn’t do anything with this notion for a few years because it seemed so obvious that I figured everyone already knew this hypothesis, or had tested it and found it was not true.”

Stern said he changed his mind a few months ago when a health care consulting firm asked him to provide input about autism.

“In preparing for this interview, I discovered that gestational diabetes was the most important identified maternal risk factor for autism, but that ‘no known mechanism could account for this,’” Stern recalled. “When I read this, I was speechless. That’s when I realized that this was not obvious to others in the field, so I decided to write this up with the hope that clinicians might become aware of this and treat their patients accordingly.”

In writing the article, Stern said he learned that the role of insulin in cognitive function is becoming more widely accepted.

“I was checking to see if insulin was known to affect synaptic function, and I learned that the nasal application of insulin is already being tested to see if it is beneficial for both Alzheimer’s and schizophrenia.”

Stern said he also found preliminary studies that indicated that low-carb diets were therapeutic for some individuals with autism and ASD.

“Based on what’s already in the literature, insulin needs to be taken seriously as a causative element in autism,” Stern said. “I hope that clinicians will take the next step and put this to a rigorous test and determine how to best use this information to benefit patients.”

Material adapted from Rice University.

Researcher Jennifer Pinto-Martin, MPH, PhD

The infants were born between September 1984 through July 1987 in Middlesex, Monmouth, and Ocean counties in New Jersey at birthweights from 500 to 2000 grams or a maximum of about 4.4 pounds.

“As survival of the smallest and most immature babies improves, impaired survivors represent an increasing public health challenge,” wrote lead author Jennifer Pinto-Martin, MPH, PhD, director of the Center Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) at Penn Nursing. “Emerging studies suggest that low birthweight may be a risk factor for autism spectrum disorders.”

Links between low birthweight and a range of motor and cognitive problems have been well established for some time, but this is the first study that establishes that these children are also at increased risk for autism spectrum disorders (ASD).

“Cognitive problems in these children may mask underlying autism,” said Dr. Pinto-Martin. “If there is suspicion of autism or a positive screening test for ASD, parents should seek an evaluation for an ASD. Early intervention improves long-term outcome and can help these children both at school and at home.”

In future studies, Penn researchers will investigate possible links between brain hemorrhage, a complication of premature birth, and autism by examining brain ultrasounds taken of these children as newborns.

The researchers, including a team at The Children’s Hospital of Philadelphia, followed 862 children from birth to young adulthood finding that five percent of the children were diagnosed with autism, compared to one percent of the general population in what researchers called “the first study to have estimated the prevalence of ASD . . . using research validated diagnostic instruments.”

Material adapted from University of Pennsylvania School of Nursing.

ASDs are a group of childhood neurodevelopmental disorders characterized by problems with social interaction, communication, and restricted and unusual behaviors. ASDs vary widely in severity and may be accompanied with or without intellectual disability. Amid a significant increase in the reported prevalence of ASDs, the Centers for Disease Control and Prevention (CDC) has recognized autism as an urgent public health concern and stressed the importance of characterizing risk factors.

“ASDs represent a diverse group of conditions that may have different causes, and children with ASDs, either with or without ID, represent opposite ends of the autism spectrum,” says Judith Pinborough-Zimmerman, Ph.D., research assistant professor in the Department of Psychiatry at the University of Utah, and first author on the study. “By identifying risk factors associated with ASDs, we may be able to gain a better understanding of the underlying causes of autism.”

Pinborough-Zimmerman and her colleagues identified children with ASD and/or ID in a three-county area surrounding Salt Lake City through the Utah Registry of Autism and Developmental Disabilities (URADD), a multiple-source, population-based surveillance program. They evaluated a variety of demographic factors and found that children with ASD but not ID were significantly more likely to be male and to have mothers of white, non-Hispanic ethnicity. Children with both ASD and ID were also more likely to be male, but were more likely to have mothers older than 34 years of age. Children who had ID but not ASD were significantly more likely to have fathers older than 34 years of age and significantly less likely to have mothers with more than 13 years of education.

“Demographic risk factors, such as male gender and parental age have been well-described,” says Pinborough-Zimmerman. “However, the way in which socioeconomic factors are associated with the development of ASDs is poorly understood.”

To investigate the link between socioeconomic factors and autism, Pinborough-Zimmerman and her colleagues examined how various measures of income changed over an eight-year period in families with a child with ASD and/or ID, as compared with the general population. The researchers were surprised to find no clear association between markers of income and the risk for ASD and/or ID, as previous studies have shown ASD to be associated with indicators of higher income and ID to be associated with indicators of low income.

“This study, despite the small sample size, is an example of the importance of exploring the many variables, that in combination, may result in an increase risk of developing ASD,” says Dr Harper Randall, Medical Director for the Division of Family Health and Preparedness, UDOH.

According to Pinborough-Zimmerman, the strength of this study lies in its broad ascertainment methods, which utilized multiple educational and health source records to include a wide spectrum of ASD cases. This study was also unique in analyzing socio demographic risk factors for ASD and ID, both independently and together.

“We hope that by identifying the many possible genetic, environmental, and socioeconomic factors that may contribute to this complex group of neurodevelopment disorders, there can be improvements in diagnosis, treatment, and prevention,” says Pinborough-Zimmerman.

Material adapted from University of Utah Health Sciences.

The study was carried out by a team led by Dr. Elisabeth Hill at Goldsmiths (University of London), Dr. Hayley Leonard (Goldsmiths) and the British Autism Study of Infant Siblings (BASIS) based at Birkbeck University of London. The researchers examined infants with a diagnosed older sibling with ASD. Siblings are known to share a higher risk of developing the disorder.

The researchers assessed the infants using a longitudinal follow-up design at 7, 14, and 24 months. Two groups of infants participated in the study: (1) 54 infants at-risk of a diagnosis of ASD based on a sibling diagnosis and (2) 50 low-risk infants without a diagnosed sibling. The infants were assessed on a range of standardised measures of motor skills. Parent reports were also documented.

Statistical analyses revealed that the at-risk group had significantly poorer motor skills than the low-risk group detected as early as 7 months old. Both gross motor skills such as the ability to hold up the head/rollover/walk and fine motor skills such as grasping and manipulating small objects were found to be poorer in the group of children at-risk for the disorder. This poorer motor ability was still evident at the 24 month assessment stage..

Dr. Hayley Leonard, the presenter of the study findings at the conference said, “These data are extremely important because even if the at-risk infants do not go on to be diagnosed with ASD, research suggests that poorer motor development could have a negative impact on their language, social and cognitive development over time. This poorer motor development could impact on their development of social skills, school achievement and longer-term employment outcomes”.

Material adapted from British Psychological Society (BPS).

After reviewing measures of attention and hyperactivity, and measures of quality of life, for over 2,000 children and adolescents with ASD, they found that over half of this group had symptoms of either attention or hyperactivity problems. More than a third had significant symptoms of both.

Children with ASD frequently have other symptoms that may compound difficulties with communication, socialization and restricted interests. More than one in three children evaluated had symptoms suggesting that they might have ADHD. Approximately one in ten of the children studied were receiving stimulant medications typically used to treat ADHD. This suggests that most of these children and adolescents with ASD and ADHD symptoms are not being treated with medications for these inattentive and hyperactive symptoms.

Children with ASD have lower adaptive functioning – the ability to get along in daily situations – than typically developing children. Not only does the presence of ADHD symptoms compromise their adaptive abilities, quality of life is further reduced.

“Identification of ADHD symptoms in children with ASD is important so that health care providers can work to treat these issues. Further research is needed to determine whether stimulant medication improves ADHD symptoms in children with ASD,” explained ATN Medical Director Daniel Coury, M.D.

Dr. Coury explained why this research is important to the ATN. “Because it’s very common for children with ASD to present other medical symptoms and diagnoses, a primary goal of the ATN is to create a model of comprehensive medical care for children and adolescents with autism, and best practices to be shared with medical practitioners throughout North America and around the world.”

Material adapted from Autism Speaks.

This study supports a growing body of evidence that early motor development and self-produced motor experiences contribute to infants’ understanding of the social world around them. Conversely, this implies that when motor skills are delayed or impaired – as in autism – future social interactions and development could be negatively impacted.

“Our findings suggest that in early development, there are more connections among different behaviors than people may expect,” said study co-author Amy Needham, a professor of psychology and Vanderbilt Kennedy Center investigator. “Early motor development is so important for infants—in this case, beginning to grasp and move objects allows infants to control their own experiences much more directly than they could before.”

Previous research has found that infants diagnosed with autism spectrum disorders show less interest in faces and social orienting. While the current study was conducted with typically developing infants, it indicates that infants who are at risk for ASD or show signs of abnormal social development may benefit from motor training as early as 3 months of age.

“Our results provide us with a new way to think about typical, and also atypical, development,” said Klaus Libertus, the study’s lead author and a research scientist at Kennedy Krieger Institute’s Center for Autism and Related Disorders. “The mind is not independent from the body, especially during development. As motor skills advance, other domains follow suit, indicating strong connections between seemingly unrelated domains. Such connections have exciting implications, suggesting that interventions could target the motor domain to foster social development.”

In the study, the researchers divided 36 typically-developing, 3-month-old infants into two groups – one receiving active motor experiences and the other receiving passive experiences. Infants in the active group were given mittens affixed with strips of Velcro, known as “sticky mittens.” The researchers observed as infants in the active group played with the “sticky mittens” for 10 minutes each day for two weeks. While wearing the mittens, a brief swipe of the infants’ arm made toys, also covered in Velcro, “stick” as if the infant had successfully grasped the object. Parents first demonstrated this by attaching the toy to the mitten, but then the toy was removed and the infant was encouraged to independently reach for the toy again.

In the passive group, infants were fitted with aesthetically similar mittens and toys, but without Velcro. Passive infants also played with the mittens and toys for 10 minutes each day for two weeks, but were only passive observers as parents provided stimulation by moving the toy and touching it to the inside of the infants’ palms.

After two weeks of daily training, the researchers tracked the infants’ eye movements while they watched images of faces and toys flash on a computer screen. Infants in the passive and active groups were compared with each other, as well as to two control groups of untrained infants comprised of non-reaching 3-month-olds and independently-reaching 5-month-olds. Researchers found the following:

• The active group showed more interest in faces rather than objects. In contrast, the passive group showed no preference.
• Infants in the active group focused on faces first, suggesting strengthening of a spontaneous preference for faces.
• When compared to the untrained control groups, the social preferences of the 3-month-old infants who experienced active training were similar to those of the untrained 5-month-olds, indicating advanced development following training.
• Finally, individual differences in motor activity observed between all 3-month-old infants in the study were predictive of their spontaneous orienting to faces. Regardless of training experiences, the more reaching attempts infants made, the stronger was their tendency to look at faces. Thus, motor experiences seem to drive social development.

“The most surprising result of our study is that we see a connection between early motor experiences and the emergence of orienting towards faces,” Libertus said. “Logically, one would predict exactly the opposite. But in the light of seeing actions as serving a social purpose, it does make sense.”

A key question researchers hope to answer next is whether these early changes will translate into future gains for these children. “Our results indicate a new direction for research on social development in infants,” said Libertus. He, along with Needham and their colleagues, will continue to observe these children to see if the social development benefits achieved during the current study are sustained one year later.

Support for this study was provided by grants from the National Institutes of Health.

Material adapted from Vanderbilt University.

The “Recurrence Risk for Autism Spectrum Disorders: A Baby Siblings Research Consortium Study” found that 19 percent of younger siblings of children with ASD developed autism, a rate significantly higher than the general population. If there were two children with ASD in the family, the risk of the third sibling developing ASD increased to more than 32 percent. The study found that the risk of an ASD diagnosis for male infants who had an older sibling with ASD was almost three times greater than the risk for female infants (26 percent compared to 9 percent). The study did not find any increase in risk associated with the gender of the older sibling, severity of the older sibling’s symptoms, or other parent characteristics such as parental age, socio-economic status or race/ethnicity.

“By pulling together data from many investigators who are studying infant siblings of children with autism, these results offer a more accurate estimate of the recurrence rate for autism in siblings,” says Autism Speaks Chief Science Officer Geraldine Dawson, Ph.D. “Surprisingly, the rate is much higher than previous estimates. This points to the important need for closely monitoring and screening siblings so that they can be offered intervention as early as possible to ensure the best possible outcome.”

The study involved 664 infants from 12 U.S. and Canadian sites, evaluated as early as 6 months of age and followed until age 36 months. This study used gold standard diagnostic methods and comprehensive assessments by expert researchers, compared to prior studies based on more narrow diagnostic criteria.

“It has been well established that siblings of children with ASD are at higher risk for developing the disorder, but our estimates of the recurrence rate had been based on much smaller samples,” explained Autism Speaks Director of Research for Environmental Sciences Alycia Halladay, Ph.D. who oversees the BSRC. “These findings emphasize the importance of family history as an autism risk factor that requires attention by parents and clinicians in tracking these infants from an early age to determine if the younger sibling develops ASD or a development disorder.”

“It’s important to recognize that these are estimates that are averaged across all of the families. So, for some families, the risk will be greater than 18.7 percent, and for other families it would be less than 18.7 percent,” said Sally Ozonoff, Ph.D., professor of psychiatry and behavioral sciences at the MIND Institute and the study’s lead author. “At the present time, unfortunately, we do not know how to estimate an individual family’s actual risk.”

The High Risk Baby Siblings Research Consortium, now engaging 25 scientists at 21 institutions in the U.S., Canada, Israel and the UK, is a partnership between Autism Speaks and the National Institutes of Health, led by the National Institute of Child Health & Human Development. Autism Speaks began funding baby sibling research in 1997 and has since committed over $7 million to this project, both in scientific research and programmatic activities. Autism Speaks also provided funding to authors Ozonoff and Young for this study.

Material adapted from Autism Speaks.

Professor Rafael Malach

By scanning the brain activity of sleeping children, the scientists discovered that the autistic brains exhibited significantly weaker synchronization between brain areas tied to language and communication, compared to that of non-autistic children.

“Identifying biological signs of autism has been a major goal for many scientists around the world, both because they may allow early diagnosis, and because they can provide researchers with important clues about the causes and development of the disorder,” says postdoctoral fellow Dr. Ilan Dinstein, a member of the group of Prof. Rafael Malach, who headed this study in the Weizmann Institute’s Neurobiology Department. While many scientists believe that faulty lines of communication between different parts of the brain are involved in the spectrum of autism disorders, there was no way to observe this in very young children, who are unable to lie still inside an fMRI scanner while they are awake.

But work by Malach’s group and other research groups pointed to a solution. Their studies had shown that even during sleep, the brain does not actually switch off. Rather, the electrical activity of the brain cells switches over to spontaneous fluctuation. These fluctuations are coordinated across the two hemispheres of the brain such that each point on the left is synchronized with its corresponding point in the right hemisphere.

As compared to the control brain (top), the autistic brain (bottom) shows weaker inter-hemispheric synchronization in several areas, particularly the superior temporal gyrus (light blue) and the inferior frontal gyrus (red).

In sleeping autistic toddlers, the fMRI scans showed lowered levels of synchronization between the left and right brain areas known to be involved in language and communication. This pattern was not seen either in children with normal development or in those with delayed language development who were not autistic. In fact, the researchers found that this synchronization was strongly tied to the autistic child’s ability to communicate: The weaker the synchronization, the more severe were the symptoms of autism. On the basis of the scans, the scientists were able to identify 70% of the autistic children between the ages of one and three.

Dinstein: “This biological measurement could help diagnose autism at a very early stage. The goal for the near future is to find additional markers that can improve the accuracy and the reliability of the diagnosis.”

Material adapted from Weizmann Institute of Science.

The report defines a set of messenger RNA (mRNA) molecules that the Fragile-X mental retardation protein (FMRP) binds in the brains of mice. Many of these mRNAs encode proteins that function at neurons’ connection points. When properly bound, FMRP prevents the translation of these mRNAs into proteins until the time is right.

“By understanding for the first time the direct targets of FMRP and its actions, we open up a whole world of potential avenues for therapies designed to make kids with Fragile X or autism better,” said Robert Darnell, a Howard Hughes Medical Institute investigator at The Rockefeller University.

“The power comes from taking two diseases with similar symptoms and looking at what is in common,” added Jennifer Darnell, also at The Rockefeller University. Of the almost 850 identified targets of FMRP, she explained, it is likely only a much smaller subset has a real impact on health or disease.

The Darnell team’s breakthrough uses a technique they developed a few years ago based on a “biochemical trick”. They use ultraviolet light to solidify the bonds between a protein, in this case FMRP, and the mRNAs it binds. Those protein-mRNA complexes could then be isolated and sequenced to reveal a “beautiful map” of the mRNA transcripts and precisely where they are bound to FMRP.

The experiments reveal that FMRP specifically binds to the protein-coding portions of those brain mRNAs. Jennifer Darnell said that distribution is unlike what they have seen before and looked much like the distribution of ribosomes, the cellular components that assemble proteins.

Further experiments suggest that FMRP acts as a “brake,” reversibly stalling ribosomes after they bind mRNA. Robert Darnell likened FMRP to the nozzle at the end of a hose. It allows the mRNA transcripts to be loaded with ribosomes in the locations where they will be needed, and when the time is right, bursts of translation (protein synthesis) can occur. That sort of tight control is likely to be critical for the formation and plasticity of neural connections, the cellular foundation for learning and memory.

Their basic scientific discoveries suggest two different overall strategies for treating Fragile X Syndrome: by lowering the activity of particular proteins normally kept under wraps by FMRP or by replacing FMRP’s ability to stall ribosomes. Notably, the Darnells say the latter is exactly what antibiotics do to slow the growth of bacteria.

“We may be able to take the edge off of the extra protein synthesis,” Jennifer Darnell said.

Ultimately, there will be more to the story, Robert Darnell added. “FMRP is one of many regulatory proteins in the neuron. It doesn’t work all by itself.”

Material adapted from Cell Press.

Fragile X syndrome is a neurodevelopmental disorder characterized by impaired social function, cognition, and speech, as well as attention deficits and anxiety.

People with Fragile X, autism or autism spectrum disorders often display social impairment including social withdrawal and anxiety and have difficulty communicating and interacting with others. Although there are behavioral and psychological interventions, there are no approved medications for the treatment of social or communication difficulties in Fragile X, autism, and autism spectrum disorders.

“The condition can be severely debilitating and this medication has the potential to play a much needed role in improving the core symptoms of fragile X syndrome and helping patients and their families achieve an improved quality of life,” said Dr. Elizabeth Berry-Kravis, pediatric neurologist at Rush and principal investigator of the study.

The study is sponsored by Seaside Therapeutics, Inc, and will test the efficacy, safety, and tolerability of the drug called STX209 (arbaclofen).

Racemic baclofen (mixture of arbaclofen and esbaclofen) is approved by the FDA to treat spasticity and stiff muscles due to cerebral palsy or other forms of brain or spinal cord injury, but arbaclofen, the more active form of baclofen, is not FDA approved.

“There is some evidence that the medication may help with social behaviors in people with developmental disabilities,” said Berry-Kravis, who is a professor of pediatrics, neurology, and biochemistry at Rush University.

Participants in the randomized, double-blind, placebo controlled phase III trial will be randomized to receive either the study drug, STX209, or a placebo. The clinical trial will include screening, treatment, withdrawal of medication, and a follow-up period. Subjects who complete the study may be eligible to enroll in a subsequent open-label study in which all subjects are treated with STX209.

STX209 has been studied in a previous small placebo-controlled trial in children and adults with fragile X syndrome and showed evidence of benefit for social withdrawal.

“Previous research has found that from one-quarter to one-half of people with fragile X have autism spectrum disorders,” said Berry-Kravis.

“This trial is exciting, because it represents the culmination of 20 years work in fragile X research since discovery of the fragile X gene in 1991,” said Kravis. “We’re not expecting this to cure fragile X or autism, but it’s a very important step in the development of new treatments.”

For more information about the clinical trial, call Crystal Hervey at 312-942-7250.

Material adapted from Rush University Medical Center.

Editorial note: BMED Report encourages all participants to discuss the research in detail with the primary investigator and to review carefully the informed consent documents, including safety issues related to experimental medications, before deciding to participate.

A drug treatment is needed that would address symptoms that are “often disabling for patients and families,” says Dr. Edwin Cook, professor of psychiatry and director of autism and genetics at UIC.

UIC is the only study site in Illinois and one of 25 sites nationwide. The study is sponsored by Seaside Therapeutics, Inc. The clinical trial will enroll approximately 150 patients diagnosed with autism spectrum disorders between ages 5 and 21 to evaluate the efficacy, safety, and tolerability of STX209 (arbaclofen).

Participants in the 22-week study will be randomized to receive either the study drug, STX209, or a placebo. The clinical trial will include screening, treatment, withdrawal of medication, and a follow-up period. Subjects who complete the study may be eligible to enroll in a subsequent open-label study in which all subjects are treated with STX209.

STX209 has been studied in children with Fragile X syndrome, a genetic disorder that is the most common identified cause of autism. Previous research has found that from one-quarter to one-half of people with Fragile X have autism spectrum disorders, said Cook, principal investigator of the UIC study.

“This trial is exciting, because it represents the culmination of 20 years work in Fragile X research,” said Cook, who describes the preliminary data leading to the STX209 study in autism as a “scientific and rational approach” to medication development.

“We’re not expecting this to cure Fragile X or autism, but it’s a very important step in the development of new treatments,” Cook said. “Finding genes is great, but it’s all about treatment.”

Cook’s UIC study team includes co-investigator Dr. Fedra Najjar, assistant professor of psychiatry, and study coordinators Sarah Youngkin and Clare Tessman.

Material adapted from University of Illinois at Chicago.

Dr. Michael Spencer, who led the study from the University’s Autism Research Centre, said: “The findings provide a springboard to investigate what specific genes are associated with this biomarker. The brain’s response to facial emotion could be a fundamental building block in causing autism and its associated difficulties.”

Previous research has found that people with autism often struggle to read people’s emotions and that their brains process emotional facial expressions differently to people without autism. However, this is the first time scientists have found siblings of individuals with autism have a similar reduction in brain activity when viewing others’ emotions.

In one of the largest functional MRI (fMRI) studies of autism ever conducted, the researchers studied 40 families who had both a teenager with autism and a sibling without autism. Additionally, they recruited 40 teenagers with no family history of autism. The 120 participants were given fMRI scans while viewing a series of photographs of faces which were either neutral or expressing an emotion such as happiness. By comparing the brain’s activity when viewing a happy verses a neutral face, the scientists were able to observe the areas within the brain that respond to this emotion.

Despite the fact that the siblings of those with autism did not have a diagnosis of autism or Asperger syndrome, they had decreased activity in various areas of the brain (including those associated with empathy, understanding others’ emotions and processing information from faces) compared to those with no family history of autism. The scans of those with autism revealed that the same areas of the brain as their siblings were also underactive, but to a greater degree. (These brain regions included the temporal poles, the superior temporal sulcus, the superior frontal gyrus, the dorsomedial prefrontal cortex and the fusiform face area.)

Because the siblings without autism and the controls differed only in terms of the siblings having a family history of autism, the brain activity differences can be attributed to the same genes that give the sibling their genetic risk for autism.

Explaining why only one of the siblings might develop autism when both have the same biomarker, Dr Spencer said: “It is likely that in the sibling who develops autism additional as yet unknown steps – such as further genetic, brain structure or function differences – take place to cause autism.”

It is known that in a family where one child already has autism, the chances of a subsequent child developing autism are at least 20 times higher than in the general population. The reason for the enhanced risk, and the reason why two siblings can be so differently affected, are key unresolved questions in the field of autism research, and Dr Spencer’s group’s findings begin to shed light on these fundamental questions.

Professor Chris Kennard, chairman of the Medical Research Council funding board for the research, said: “This is the first time that a brain response to different human facial emotions has been shown to have similarities in people with autism and their unaffected brothers and sisters. Innovative research like this improves our fundamental understanding of how autism is passed through generations affecting some and not others. This is an important contribution to the Medical Research Council’s strategy to use sophisticated techniques to uncover underpinning brain processes, to understand predispositions for disease, and to target treatments to the subtypes of complex disorders such as autism.”

Material adapted from University of Cambridge.

Reference
The paper “A novel functional brain imaging endophenotype of autism: the neural response to facial expression of emotion,” is scheduled for publication in the July issue of Translational Psychiatry.

Researcher Lisa Croen, PhD

“The prevalence of autism spectrum disorders (ASDs) has increased over recent years,” the authors write as background information in the article. “Use of antidepressant medications during pregnancy also shows a secular increase in recent decades, prompting concerns that prenatal exposure may contribute to increased risk of ASD.”

To evaluate if prenatal exposure to antidepressants, including selective serotonin reuptake inhibitors (SSRIs), is associated with an increase in ASD, researchers examined medical records for children drawn from the Childhood Autism Perinatal Study conducted by Kaiser Permanente Medical Care Program in Northern California. The authors included 298 children with ASD (case group) and their mothers, and 1,507 control children and their mothers in the study.

Twenty mothers of children in the case group (6.7 percent) and 50 mothers of children in the control group (3.3 percent) had at least one prescription for an antidepressant in the year prior to the birth of the study child. Of the 20 case mothers who were prescribed antidepressants, 13 (65 percent) were prescribed SSRIs only, two (10 percent) were prescribed an SSRI in combination with another antidepressant and five (25 percent) were prescribed one or more non-SSRI antidepressants only. Of the 50 control mothers who were prescribed an antidepressant, 25 (50 percent) were prescribed SSRIs only, nine (18 percent) were prescribed an SSRI in combination with another antidepressant and 16 (32 percent) were prescribed one or more non-SSRI antidepressants only.

After adjusting for maternal and birth factors, mothers of children with ASD were twice as likely to have at least one antidepressant prescription in the year prior to delivery. When compared with women with no antidepressant prescription during the study period, those with a prescription for a SSRI were more than twice as likely to have a child later diagnosed with ASD. This association was not seen for the small group of women who were prescribed a non-SSRI antidepressant only.

Additionally, after adjustment for a history of depression during the year prior to delivery, SSRI exposure during the first trimester remained significantly associated with risk of ASD, as was a history of SSRI exposure at any point during the year prior to delivery. Conversely, no association was seen between risk of ASD and the indication for treatment (mother having a history of depression or any mental health disorder) for the year prior to delivery.

“Although the number of children exposed prenatally to selective serotonin reuptake inhibitors in this population was low, results suggest that exposure, especially during the first trimester, may modestly increase the risk of ASD,” the authors conclude. “We recommend that our findings be considered as preliminary and treated with caution, pending results from further studies designed to address the very complex question of whether prenatal exposure to SSRIs may be etiologically linked to later diagnoses of ASDs in offspring.”

Material adapted from JAMA.

Reference
Arch Gen Psychiatry. Published online July 4, 2011. doi:10.1001/archgenpsychiatry.2011.73.

Researcher Joachim Hallmayer, MD

Current estimates suggest that 40 of every 10,000 children have autism, and prevalence rates for ASDs are about 1 percent, according to background information in the article. Studies of siblings have found a concordance rate (the likelihood that if one child has the disorder, others will as well) of up to 14 percent. The authors note that in previous studies of twins, concordance rates for autism were relatively high for identical (monozygotic) twins, but nonexistent for fraternal (dizygotic) twins.

Further, studies that depended on differing methods of diagnosis have resulted in a broad range of estimates of autism’s heritability. “However,” the authors state, “none of these more recent studies included structured clinical assessments by both parental interview and direct child observation, which is the contemporary standard for establishing the diagnosis of autism or ASD.”

In the California Autism Twins Study, researchers used data from the California Department of Developmental Services to identify potential participants. The researchers assessed twin pairs in which at least one child had an ASD diagnosis, using the Autism Diagnostic Interview–Revised, a structured parent interview and the Autism Diagnostic Observation Schedule, as well as other tests to determine verbal and nonverbal cognitive abilities. Two diagnoses were utilized: strict autism and ASD. Children with autism or ASD that was included in the initial data and confirmed by the researchers were considered “probands.”

The final analysis included 54 pairs of identical twins and 138 pairs of fraternal twins (of which 80 were comprised of a boy and a girl). Researchers found the likelihood of both children having autism or ASD was higher among identical twins than among fraternal twins. They also used modeling to estimate how much of the risk could be attributed to genetic factors. This analysis demonstrated that more than half of the variance in risk was probably explained by shared environmental factors versus less than 40 percent of the risk owing to genetic heritability.

“The results suggest that environmental factors common to twins explain about 55 percent of the liability to autism,” the authors write. “Although genetic factors also play an important role, they are of substantially lower magnitude than estimates from prior twin studies of autism…. The finding of significant influence of the shared environment, experiences that are common to both twin individuals, may be important for future research paradigms.”

Material adapted from JAMA.

Reference
Arch Gen Psychiatry. Published online July 4, 2011. doi:10.1001/archgenpsychiatry.2011.76.

“Enhanced Polyubiquitination of Shank3 and NMDA Receptor in a Mouse Model of Autism” details a new SHANK3 mutant mouse and demonstrates how this autism-associated gene affects brain functioning. Examining the genetic causes of autism, Bangash worked with mentor Paul Worley, M.D. of Johns Hopkins University, and Kouser worked with mentor Craig Powell at the University of Texas Southwestern Medical Center at Dallas to refine a mouse model to study the gene SHANK3 and investigate its implications for autism. Their work specifically shows that the gene is involved in how neurons communicate at synapses. When this gene mutation was recreated in a mouse, the animals had significant changes in a neurotransmitter, glutamate, which regulates communication between neurons in the brain and results in behavioral deficits consistent with symptoms of autism.

“This is significant published research from our Weatherstone Fellows portfolio. We are pleased to see the fruits of their efforts so soon, and the exceptional caliber of this work is representative of the excellence in this group of scientists who are pursuing the next generation of autism research,” said Geraldine Dawson, Ph.D., chief science officer for Autism Speaks.

Cheryl Weatherstone Vance recently told a gathering of Weatherstone fellows, “My father, along with the Stavros Niarchos Foundation, wanted the brightest minds in the country to find answers to the mysteries of autism. You are on an incredible journey as your research will benefit countless lives. It is exciting to see the progress you have made already. All of you are presented with a great challenge and I am honored that you have chosen autism as your field of research. It is through your work that I can have hope that there will be a cure for every child and their families who are affected by autism.”

Autism Speaks is pleased to announce the 2011 Class of Dennis Weatherstone Pre-Doctoral Fellows. These eight fellows were selected out of 50 proposals from a highly qualified and enthusiastic field of candidates. Projects were selected for funding based on the strengths of the training plan, research strategy, mentor’s qualifications and the relevance of the topic to Autism Speaks’ research priority areas.

Behavioral Neuroscience is the focus of Cara Damiano, working with mentor Gabriel Dichter at University of North Carolina on Behavioral and Neural Correlates of Reward Motivation and Jilian Filliter working with Shannon Johnson at Dalhousie University will study Preference Acquisition in Children and Adolescents.

Identifying subtypes of autism is the focus of Rui Luo working with Daniel Geschwind at University of California Los Angeles on Genome-wide Expression Profiling Data Analysis and Nir Oksenberg working with mentor Nadav Ahituv at University of California San Francisco on Deciphering the Function and Regulation of AUTS2.

Dissemination of best practices, a strategic goal of Autism Speaks, will be advanced through the work of Frances Martinez-Pedraza who will work with mentor Alice Carter at University of Massachussets on Dissembination of Screening to Underserved Culturally-Diverse Families and at Michigan State University, fellow Allison Wainer will work with mentor Brooke Ingeroll on Internet-based Program to Teach Naturalistic Intervention to Parents.

Kristopher Nazor will work in developmental biology on Stem Cell Platform for Identification of Defects with mentor Jeanne Loring at Scripps Research Institute. Using stem cells created from skin tissue to create neurons and understand the biological basis of autism will be the focus of Sean Johnston at University of Wisconsin Madison under mentor Ronald Raines.

Made possible by a multi-year grant from the Stavros Niarchos Foundation named in honor of former J.P. Morgan CEO Sir Dennis Weatherstone. The fellowship awards provide highly qualified candidates with exceptional research training opportunities across various areas related to the study of ASD. Autism Speaks established this fellowship program in 2008 to encourage the most promising young scientists to establish autism research as their chosen career path and support the growth of a promising cadre of young autism scientists. The Weatherstone fellow abstracts are found on Autism Speaks new Science Grant Search function at http://www.autismspeaks.org/science/grant-search.

Material adapted from Autism Speaks.

The “Hacking Autism” innovative designs aim to facilitate and accelerate technology-based ideas to open up learning, communication and social possibilities, and to help give those with autism a voice.

“Innovations in technology are moving forward the race to find solutions to improve daily life for individuals with autism,” stated Autism Speaks Chief Science Officer Geraldine Dawson, Ph.D. “Input from the community will accelerate designers and innovators’ creative thinking to best apply technology to autism in a way that has the potential to make a significantly positive impact for individuals with autism where they need it most.”

“Technology has the power to improve lives, and our hope is to work with the developer community to find ways that technology, such as touch-enabled computers, tablets, and software, can advance communications and learning experiences for individuals with autism and their families,” said Phil McKinney, vice president and chief technology officer of the Personal Systems Group, HP. “We are excited that the Autism Speaks and the Flutie Foundation organizations are joining HP in supporting HackingAutism.org.”

Together, the groups announced the appointment of the Hacking Autism Advisory Committee, which will select for development ground-breaking, touch-enabled applications submitted by the autism community for the autism community. The committee is composed of leading technology and autism experts, including McKinney; David Canora, principal technology specialist, Walt Disney Parks and Resorts, and chairman, Quest Inc.; Chris Mertens, vice president, HP; Autism Speaks Vice President of Scientific Affairs Andy Shih, Ph.D.; Simon Wallace, Ph.D., Autism Speaks director of scientific development Europe; Peter Bell, Autism Speaks executive vice president for programs and services; renowned advocate and author John Elder Robison; Jim St. Leger, Technology Marketing Manager, Intel; and certified speech and language pathologist and advance clinician Kate Grandbois, M.S., CCC-SLP, Spaulding Outpatient Center for Children.

“So many individuals with autism who struggle with verbal communication are able to open up new doors to social interaction when they are able to use tools such as touch applications,” explained Canora, who is also dad to a son with autism. “Parents are always looking for new strategies to engage their children with the people and world around them and technology has so much potential to do that.”

“We are so pleased to partner with HP and the Flutie Foundation,” added Dr. Wallace. “Autism Speaks has been committed to innovations in technology to creatively adapt and promote the use of technologies to meet needs of those with autism. ‘Hacking Autism’ will significantly accelerate translational technology, from bench top to commercial development.”

“We’re excited to partner with HP and Autism Speaks on this cutting-edge project,” said Doug Flutie, co-founder of the Doug Flutie, Jr. Foundation for Autism. “Through our Laurie Flutie Computer Initiative and our long-time partnership with HP, we have been able to assist hundreds of families and schools by providing them with computers. ‘Hacking Autism’ will allow the autism community to directly communicate their ideas with HP on what its needs are for technology. It’s not often that a mom or dad, or a teacher who works with a child with autism, gets to tell a software designer what type of tools they need to enhance their loved one’s life. We feel that this type of collaboration has the ability to really improve the learning and communication experience for people on the autism spectrum.”

“Hacking Autism” will culminate in October 2011 at the HP Hackathon and the new technologies developed will be included in its library of applications.

Material adapted from Autism Speaks.

In her thesis, Dewrang investigated how individuals with Asperger syndrome aged 14-24 years old perceive themselves relative to their diagnosis. The thesis is based on interviews, tests and self-evaluations. A questionnaire for parents also resulted in important descriptions of these individuals’ behaviour and development from infancy onwards.

The results show first and foremost that the similarities are greater than the differences when the Asperger group and the comparison group describe their lives.

“But the differences that do exist are vital for understanding how people with Asperger syndrome stand the best chance of getting by,” says Dewrang.

The Asperger group were as content with themselves and their lives as the comparison group. But they found it harder to build relationships with other people, and their plans for the future were less “adventurous.” Parents and siblings were more present in their lives than is normal for this age group even after they had left home.

On the other hand, those with Asperger’s syndrome were just as good at social cognition as the comparison group when they had to explain why the key person in a story reacted in a certain way. However, the limited ability to theoretically understand other peoples’ thoughts and feelings made it difficult to maintain relationships in real life.

Material adapted from University of Gothenburg.

Reference
Dewrang, P. & Dahlgren Sandberg, A. (2011). Repetitive behaviour and obsessive-compulsive features in Asperger syndrome: Parental and self-reports. Research in Autism Spectrum Disorders, 5, 1176-1186.

Eric Courchesne, PhD

Eric Courchesne, PhD, professor of neurosciences at the UC San Diego School of Medicine, and colleagues in Israel and Pittsburgh report that language areas located in the right and left sides of the brain are less synchronized in toddlers with autism than in toddlers displaying either language delay problems or typical development. The strength of synchronization was associated with individual language and communication abilities: the weaker the synchronization, the more severe the communication difficulties exhibited by the autistic child.

“Neural synchronization refers to the coordinated timing of neural activity across distinct brain areas,” said Ilan Dinstein, PhD, a neurobiologist at the Weizmann Institute of Science in Rehovot, Israel, a member of the UCSD Autism Center of Excellence, and first author of the study.

“In a normal brain, neurons in separate areas belonging to a system with a particular function, such as vision or language, always stay in sync, even during sleep. Our study shows that in most brains of toddlers with autism this ‘sync’ is significantly weaker in brain areas that are responsible for language and communication abilities. Many things need to be set up right during brain development to enable normal sync between different brain areas. The wiring between the brain areas needs to be right and the neurons within each brain area need to send and receive their messages properly.”

The findings, if corroborated by further research, could have significant impact, Dinstein said.

“It would be a biological rather than a behavioral measure that could be used to diagnose autism at a very young age – around one year. The functional magnetic resonance image (fMRI) scan would not identify all of the individuals with autism, but it would be helpful in revealing the majority of individuals. The results also tell us that significant differences in the biology of language areas are apparent during very early stages of autism development. It will help focus further research into the brain differences that underlie autism.”

Though the exact cause of autism remains unknown, it is hypothesized that the neurological disorder – which is marked by impaired social and communications skills, usually manifesting itself in the first few years of life – arises from the development of abnormal neural networks with irregular connectivity and synchronization.

Autism is a developmental disorder that progresses with time. It is currently impossible to identify autism at birth and diagnoses, which are entirely based upon observed behavioral symptoms, are typically performed only after the age of 3. These facts help make the study of how autism develops particularly challenging. Affected toddlers are prone to incessant movement and random, uncontrolled behaviors, both of which can disrupt efforts to measure brain function and structure using different imaging techniques.

To sidestep these difficulties, the UCSD scientists studied toddlers’ brains at night while they were sleeping. This novel approach meant toddlers with severe autism, who are often left out of studies due to their challenging behaviors, could be included, thus permitting scientists to successfully test the strength of brain synchronization in children with different levels of development and identify the brain areas that exhibited weak synchronization in those with autism.

“We hope that this work will be one of several enlightening steps leading to a fuller understanding of the underlying biology of autism during early development,” said Dinstein. “Such an understanding is critical for developing the necessary diagnostic and therapeutical tools that are so needed for successful early intervention.”

Co-authors of the paper include Karen Pierce and Eric Courchesne, Autism Center of Excellence and the Department of Neurosciences, both at UCSD; Lisa Eyler, Autism Center of Excellence and Department of Psychiatry, UCSD; Stephanie Solso, Autism Center of Excellence, UCSD; Rafael Malach, Department of Neurobiology, Weizmann Institute of Science; Marlene Behrmann, Department of Psychology, Carnegie Mellon University, Pittsburgh.

Material adapted from University of California, San Diego Health Sciences.

About autism
Autism is a neurological disorder typically appearing in the first few years of life. It affects the brain’s normal development of social and communication skills. Symptoms include impaired or lost language and social skills, heightened physical sensitivities and compulsive or repetitive behaviors.

The condition is linked to abnormal biology and chemistry in the brain, but the exact causes for these abnormalities is not known, though it is likely a combination of genetic and environmental factors. The term autism broadly covers a range of complex neurodevelopment disorders known as autism spectrum disorder or ASD. The total number of children with ASD is not known, but experts estimate three to six children in every 1,000 have an ASD condition. Boys are four times more likely to have ASD than girls.

Material adapted from University of California, San Diego Health Sciences.

Paul Worley, M.D.

The Johns Hopkins team further reveals how a mutation of Shank3 leads to altered communication between brain cells at synapses — those gaps between cells across which electrical information flows.

The team first identified Shank proteins in studies of synaptic proteins that are regulated by neuronal activity. The scientists say they were motivated to make the new mouse after other investigators showed that a subset of children with autism carries mutations of the Shank3 gene. Patients with a mutation that prevented Shank3 proteins from forming complexes at the synapse had particularly severe disease despite having one mutant and one normal copy of Shank3. To refine a mouse model of the disease that mimicked the human mutation, the researchers altered one copy of Shank3 and left intact a normal copy of the gene.

“We hope our model of accelerated protein degradation will be applicable to other genetic causes of autism and, perhaps, schizophrenia” says Paul Worley, M.D., a professor of neuroscience at the Johns Hopkins University School of Medicine. “Behavioral changes in these mice can be understood to be the result of the changes in synaptic proteins.”

Ali Bangash, a graduate student of biological chemistry and molecular biology working in Worley’s lab, used biochemical methods to survey the levels and activity of the Shank3 protein in sections of brain from the Shank3 mutant mouse. He discovered that the amount of normal Shank3 protein was dramatically reduced in the new Shank3 mutant. In addition, the mutant Shank 3 protein seemed to cause any normal Shank3 protein to be targeted for rapid degradation. In fact, the amount of Shank3 that makes its way to where it is supposed to be (at synapses in the brain) is reduced by 90 percent compared to normal mice, according to Worley.

“By mutating one copy of Shank3, we didn’t simply lose half of the amount of protein that normally would be produced, we lost more of good protein,” Worley says, adding that the team also noted behavioral and electrophysiological changes when they mutated one copy of Shank3 in mice.

In one experiment, the researchers electrically stimulated nerve cells from the mouse brains, assessed the strength of synapses from Shank3 mutants and compared these to brain tissue from normal, wild-type mice. The scientists found that the ratio of two different types of proteins vital to memory and learning was out of whack in Shank3 mutants.

The team also assessed the behaviors of the Shank3 mutants by using social interaction tests and comparing them to wild-type mice. In one test, a Shank3 mutant was placed with another mouse in a cage, leaving both free to explore their surroundings. The Shank3 mutant mouse spent much of the time shying away from social interaction. The wild-type showed an increased level of interest, indicated by time spent sniffing the Shank3 mutant. However, when the Shank3 mutant was allowed to roam free while the other mouse was confined under a dome with slits, the Shank3 mouse showed increased interest, exploring the immobilized mouse more than a wild-type did under the same circumstances. The investigators say this behavior is consistent with characteristics of an autism-like disorder.

In another test, a younger mouse was introduced three times to a Shank3 mutant and to a wild-type mouse. The wild-type and Shank3 mouse both spent less time exploring the young mouse on each successive interaction, indicating they got used to each other. When a different “surprise” mouse of the same age and genetic background was brought in, the wild-type mouse re-explored the animal with renewed interest, apparently recognizing it as “new.” The Shank3 mutant, also apparently recognizing it as new, not only re-explored, but also became markedly aggressive, nipping, and biting the “surprise” mouse, a behavior that the investigators concluded was also autism-like.

Worley says it is “exceedingly challenging” to make an accurate animal model of autism, a complex neurobiological disorder that inhibits a person’s ability to communicate and develop social relationships.

Autism spectrum disorders are diagnosed in one in 110 children in the United States, and one in 70 boys. According to Autism Speaks, North America’s largest autism science and advocacy organization, the prevalence of autism has increased 600 percent in the past two decades. The Centers for Disease Control and Prevention have called autism a national public health crisis, the cause and cure of which remain unknown.

This work was supported by National Institute of Neurological Disorders and Stroke, National Institute of Mental Health, Autism Speaks, National 973 Basic Research Program of China, The Autism Science Foundation, The Hartwell Foundation, and the NIDCD Intramural Program.

In addition to Worley and Bangash, other Johns Hopkins authors are Joo Min Park, Tatiana Melnikova, Soo Kyeong Jeon, Deidre Lee, Sbaa Syeda, Juno Kim, Joshua Schwartz, Jian Cheng Tu, Jia-Hua Hu, David J. Linden, Alena Savonenko, and Bo Xiao.

Authors from Sichuan University, Chengdu, China, are Dehua Wang, Yiyuan Cui and Xia Zhao. Authors from the University of Texas Southwestern Medical Center are Mehreen Kouser, Haley E. Speed, Craig M. Powell and Sara E. Kee. And, from the National Institutes of Health, Ronald S. Petralia.

Material adapted from Johns Hopkins Medicine.

Professor Simon Baron-Cohen

Professor Simon Baron-Cohen, Director of the Autism Research Centre (ARC) at the University of Cambridge, led the study (which was conducted in the Netherlands) with Dr. Rosa Hoekstra, a Dutch autism researcher based at ARC and The Open University.

The researchers predicted that autism spectrum conditions (ASC) would be more common in populations enriched for ‘systemizing’, which is the drive to analyze how systems work, and to predict, control, and build systems. These skills are required in disciplines such as engineering, physics, computing, and mathematics.

The team had previously discovered evidence for a familial association between a talent for systemizing and autism in that fathers and grandfathers of children with ASC are over-represented in the field of engineering. The team had also previously found that mathematicians more often have a sibling with ASC, and students in the natural and technological sciences, including mathematics, show a higher number of autistic traits.

The researchers tested for differences in the prevalence of ASC in school-aged children in three geographical regions in the Netherlands: Eindhoven, Haarlem, and Utrecht-city. The region Eindhoven was selected because it is rich in information-technology (IT) having the Eindhoven University of Technology there, as well as the High Tech Campus Eindhoven, where IT and technology companies such as Philips, ASML, IBM, and ATOS Origin are based. (The Philips factory has been in Eindhoven since 1891. Since then, the region has attracted businesses in IT and technology.)

The growth of the High Tech Campus Eindhoven has led to Eindhoven becoming a major technology and industrial hub: 30% of jobs in Eindhoven are now in technology or ICT, in Haarlem and Utrecht this is respectively 16 and 17%.

The two control regions were selected because they have similar size populations and a similar socioeconomic class. Schools in each region were asked to provide the number of children enrolled, the number having a clinical diagnosis of ASC and/or two control neurodevelopmental conditions (dyspraxia and ADHD). The participating schools in the three regions provided diagnostic information on a total of 62,505 children. The researchers found school-reported prevalence estimates of ASC in Eindhoven was 229 per 10,000, significantly higher than in Haarlem (84 per 10,000) and Utrecht (57 per 10,000), whilst the prevalence for the control conditions were similar in all regions.

Simon Baron-Cohen commented: “These results are in line with the idea that in regions where parents gravitate towards jobs that involve strong ‘systemizing’, such as the IT sector, there will be a higher rate of autism among their children because the genes for autism may be expressed in first degree relatives as a talent in systemizing. The results also have implications for explaining how genes for autism may have persisted in the population gene pool, as some of these genes appear linked to adaptive, advantageous traits.”

Rosa Hoekstra added: “We need to conduct a follow-up study to validate the diagnoses and to test the alternative explanations for the elevated rate of autism in Eindhoven, including the possibility that children with autism may more often remain undetected in the two other regions. These results are important findings in the field of autism epidemiology, since they suggest regional variation in autism prevalence. In our follow-up study we plan to study the causes of this variation in more detail. This will help local authorities plan services appropriately for the number of children with autism.”

The Cambridge research team also included Martine Roelfsema (a Dutch graduate student), Sally Wheelwright, and Dr. Carrie Allison (experts in autism screening), and Professor Carol Brayne and Dr. Fiona Matthews (experts in public health research and biostatistics).

Material adapted from University of Cambridge.

Additional Information
1. Authors: Martine T. Roelfsema, Rosa A. Hoekstra, Carrie Allison, Sally Wheelwright, Carol Brayne, Fiona E. Matthews, Simon Baron-Cohen (2011). Are autism spectrum conditions more prevalent in an information-technology region? A school-based study of three regions in the Netherlands. Journal of Autism and Developmental Disorders, DOI 10.1007/s10803-011-1302-1

2. Author affiliations: Autism Research Centre, Department of Psychiatry, Cambridge University, Cambridge CB2 8AH, UK, (www.autismresearchcentre.com); Department of Life Sciences, The Open University, Milton Keynes, UK; Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK; MRC Biostatistics Unit, Institute of Public Health, Cambridge UK

3. Funding sources: Research grants from the Medical Research Council (UK); Target Autism Genome; the Nancy Lurie Marks Family Foundation; NIHR CLAHRC for Cambridgeshire and Peterborough NHS Foundation Trust; the Erasmus fund, the Bekker la Bastide fund and the University of Amsterdam and the Netherlands Organisation for Scientific Research (NWO Rubicon)

4. The Eindhoven region comprised the municipalities of Eindhoven, Veldhoven and Waalre. The Haarlem region comprised the municipalities of Haarlem and Haarlemmermeer. The Utrecht region comprised Utrecht-city. The populations of Eindhoven, Haarlem and Utrecht regions respectively are 269,504, 285,215 and 288,401. The three regions have a similar average income per household, a similar percentage of children with special needs, and similar rates of individuals with mental health conditions.

5. For almost 100 years the Medical Research Council has improved the health of people in the UK and around the world by supporting the highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize winners and sustains a flourishing environment for internationally recognised research. The MRC focuses on making an impact and provides the financial muscle and scientific expertise behind medical breakthroughs, including one of the first antibiotics penicillin, the structure of DNA and the lethal link between smoking and cancer. Today MRC funded scientists tackle research into the major health challenges of the 21st century. www.mrc.ac.uk

Autism is a spectrum disorder characterized by repetitive behaviors and impaired language, communication, and social interactions. According to the Centers for Disease Control and Prevention, it is estimated that as many as one in every 110 children is affected by autism.

“With the extraordinarily high prevalence of autism, you would think there would be an objective diagnosis for the disorder,” said Joy Hirsch, Ph.D., a professor at Columbia University Medical Center and director of the Functional MRI Laboratory. “However, the diagnosis of autism currently remains limited to parent and clinician observation of missed developmental milestones.”

In the study, researchers performed fMRI exams on 15 control children (mean age: 12.1) and 12 language-impaired and age-matched children with autism (mean age: 12.4). Using fMRI, the researchers were able to measure neural activity in working brain tissues, while the children listened to recordings of their parents talking to them.

Activation levels during passive stimulation were measured within two regions of the brain: the primary auditory cortex (A1) and superior temporal gyrus (STG), a region associated with sentence comprehension. Brain activation maps for each patient were then computed using statistical linear modeling.

Activity in the A1 region of the brain did not differ between autistic and control patients. However, activation within the STG was greater for control children relative to autistic patients.

“These findings first tell us that the autistic children in our study appeared normal with respect to the primary auditory system,” Dr. Hirsch said. “But it appears that the STG in the autistic brains was not as sensitive to the language narratives as was the STG in the brains of the typical children.”

An additional 27 children with autism undergoing routine MRI exams with sedation were also included in the study. Using a similar analysis of sedation-adjusted values from the control group, the researchers identified 26 of 27 (96 percent) sedated patients with autism.

“This study suggests that fMRI acquired during listening to a language narrative can be used to distinguish children with autism from those without,” Dr. Hirsch said. “Based on these initial findings, future studies using these or similar fMRI methods may result in an early and objective imaging indicator for autism.”

Some children with autism spectrum disorders can benefit from intensive behavior therapy, but early intervention is key.

“The need for an early, objective diagnosis is enormous,” Dr. Hirsch said.

Collaborating with Dr. Hirsch were Grace Lai, Ph.D., Harry D. Schneider, M.D., and Johanna C. Schwarzenberger, M.D.

Material adapted from Radiological Society of North America.

Reference
Joy Hirsch, Grace Lai, Ph.D., Harry D. Schneider, M.D., and Johanna C. Schwarzenberger, M.D. (2011). “Speech Stimulation during Functional MR Imaging as a Potential Indicator of Autism.” Radiology (August).

Not only are there no good screening tools or effective treatments but there is no evidence yet that routine screening does more good than harm, said Dr. Jan Willem Gorter, a researcher in McMaster’s CanChild Centre for Childhood Disability Research and associate professor of pediatrics.

Contrary to the McMaster researchers’ findings, the American Academy of Pediatrics recently recommended that screening for autism be incorporated into routine practice, such as a child’s regular physician check-up, regardless of whether a concern has been raised by the parents.

Autism, or the autism spectrum disorders (ASDs), is a group of serious neurodevelopmental disorder with major, life-altering implications. Its symptoms include differences and disabilities in many areas, including social, communication skills, fine and gross motor skills, and sometimes intellectual skills.

During the past three decades, the prevalence of autism has risen dramatically to 11 cases per 1,000 school-aged children from 0.8 cases per 1,000. Reasons for this increase vary: improved detection, changes in diagnosing the disorder or an actual increase. The disorder is more common in males with a 4:1 male-to-female ratio.

For the study, McMaster researchers conducted a literature search to assess the effectiveness of community screening programs for autism.

“None of the autism screening tests currently available has been shown to be able to fulfill the properties of accuracy, namely high sensitivity, high specificity, and high predictive value (proportion of patients with positive test results who are diagnosed correctly) in a population-wide screening program,” researchers said.

Gorter said that unlike breast cancer screening, no autism screening programs have been studied in randomized controlled trials. “There is no solid evidence on which to base the recommendations of the American Academy of Pediatrics.”

“None of the autism screening tests for the general population that we have today have proven accuracy,” said Gorter. “That is, they aren’t good enough to accurately detect children who have autism or to accurately detect those who don’t.”

Gorter said the study is a “call for action.”

At this time, the researchers called community screening of all preschoolers premature. Alternatively, they recommend careful surveillance and assessment of all preschoolers who show signs of language, social and cognitive problems.

Material adapted from McMaster University.

The study — led by Matthew State, M.D., Ph.D., the Donald J. Cohen Associate Professor of Child Psychiatry, Psychiatry and Genetics — looked at more than 1,000 families in which there was a single child with an autism spectrum disorder, an unaffected sibling, and unaffected parents. The team, including postdoctoral fellow and first author Stephan Sanders from Yale, compared individuals with autism to their siblings to determine what types of genetic changes distinguished the affected child from the unaffected child.

“Thanks to an ambitious collaboration among a large group of autism researchers from around the country, supported by the Simons Foundation, we were able to focus on an ideal study population,” said State, who is co-director of the Yale Program on Neurogenetics. “It made all the difference in our ability to identify several regions of the genome clearly contributing to autism.”

One of the most intriguing of these findings points to the same small section of the genome that causes Williams syndrome — a developmental disorder marked by high sociability and an unusual aptitude for music.

In autism, there is an increase in the chromosomal material, an extra copy of this region, and in Williams syndrome, there’s a loss of that same material,” said State. “What makes this observation particularly interesting is that Williams syndrome is known for a personality type that is highly empathetic, social, and sensitive to the emotional state of others. Individuals with autism often have difficulties in the opposite direction. This suggests that there is an important key in that region to understanding the nature of the social brain.”

State and his team also found about 30 other regions in the genome that are very likely contributing to autism and are focused on about six of those regions that showed the strongest evidence. “We’re now moving on to a second phase of the study looking at an additional 1,600 families and should be able to identify multiple new regions that are strongly implicated in autism,” he said.

Sanders and State are optimistic about the new findings, pointing out that genetics is the first step to understanding what’s really going on at the molecular and cellular level of the brain. “We can use these genetic findings to begin unraveling the underlying biology of autism,” said Sanders. “This will help tremendously in the effort to identify new and better approaches to treatment.”

Two other studies published in the June 9 issue of Neuron report on the same families studied by State, Sanders and their co-authors. One of these, by a group at Cold Spring Harbor Laboratory in New York, paints a very similar picture — that autism is a highly genetically diverse disorder and that sporadic changes in the structure of the genome present only in the affected individuals and not in other families often play a key role. The other study, by researchers at Columbia University, suggests that although hundreds of genes may be involved in autism, they appear to disrupt a common molecular network involved in the mobility of brain cells and development of synapses between them.

Additional Yale authors on the study include Gulhan Ercan-Sencicek, Michael Murtha, Abha Gupta, Kaya Bilguvar, Murim Choi, Nicole Davis Wright, Nicholas DiLullo, Thomas Fernandez, Gerald Goh, Kyle Meyer, John Murdoch, Gordon Ober, Melanie Raubeson, Youeun Song, Murat Günel, Richard Lifton and Shrikant Mane. The following authors participated in the study at Yale but are now at other institutions: Christopher Mason, Rahul Dhodapkar, Vikram Fielding-Singh, Daniel Fishman, Sindhuja Kammela, Brian O’Roak, Rebecca Pottenger and Ilana Yurkiewicz.

Material adapted from Yale University.

Reference
Neuron, Vol. 70, Issue 5 (June 9, 2011).

The study, along with an accompanying paper exploring the possible brain and neuronal pathologies to which the observed CNVs and other genetic anomalies may give rise, appears June 9 in the journal Neuron. The work was led by Professor Michael Wigler of Cold Spring Harbor Laboratory (CHSL), a pioneer in the analysis of genomes and a developer of key technologies that have made such analysis possible, in collaboration with Dennis Vitkup of Columbia University; Dan Levy, Michael Ronemus, Ivan Iossifov and Sarah Gilman of CSHL; and others.

“The causes of autism when fully fleshed out are likely to be very diverse,” Wigler says, “some of which may be treatable much more readily than others. However, the diversity of causes implies that an effective future treatment for one form of ASD may be specific only for a narrow subset of those affected.”

Four years ago, Wigler and colleagues began to publish findings about the genetics of autism that surprised many experts in the field. Among other things, they noted the prevalence of “de novo” genetic mutations in affected children. These are mutations that did not appear in either parent and hence must have arisen spontaneously. In 2008, Wigler proposed that such cases, characterized by changes in gene copy number – duplicated or deleted genome segments that leave an individual with extra or missing copies of one or more genes – likely account for at least half of ASD cases.

There is little doubt that certain genetic mutations carried by an unaffected parent can be transmitted to a child and cause the illness. Wigler, however, proposed a “unified theory” of autism genetics that suggested such cases only account for about 25% of the total.

The team used a novel form of analysis called NETBAG to identify large biological networks of genes affected by rare spontaneous mutations in autism. Rendered as “clusters,” the genes within the CNVs have vital functions in early brain development. Clusters “A” and “B” shown here (“A”: genes from CNVs that hit ~ 1 gene; “B”: from CNVs that hit ~ 2 genes) include genes known to be involved in synaptogenesis, the formation of communication junctions between neurons. (click to enlarge)

Rare and ultra-rare CNVs – and their possible biological consequences
The new study affirms the team’s earlier data on the relative importance of non-inherited, spontaneously occurring CNVs as likely causal factors in autism. Using a newly assembled sample population called the Simons Simplex Collection which included about 1000 families, consisting of both birth parents and in most cases two children, one with ASD and the other unaffected, Wigler and colleagues saw the earlier-observed effect, only “this time on a much larger scale.” The new sample collection is deemed very important by the research team. It intentionally excludes families with more than one child with ASD (“multiplex families”) since such cases are almost always inherited. A sample composed only of “simplex” families makes possible a much more accurate comparison of the relative frequency of spontaneous and inherited causal mutations.

Using a refined version of a technique called comparative genomic hybridization, but using detection devices called microarrays that were about four times as powerful as those used in prior studies, along with a suite of powerful quantitative analysis tools, the team was able to consistently resolve much smaller genomic irregularities than previously possible. This revealed a significantly greater number of genome areas where spontaneous DNA deletions and duplications “hit” genes thought to contribute substantially to ASD.

The team estimates a minimum of 250 to 300 places in the genome where CNVs give rise to ASD. Most of the CNVs were only seen once and are classified, individually, as rare. This is a potential source of confusion since these rare events, taken in total, are the source of at least half of all autism, if Wigler’s theory is correct.

As the team notes in their paper, it is still very difficult to make the connection between the areas that the de novo CNVs hit and the genes these areas harbor. Nor is it clear what role those genes have in perturbing the biology of the developing brain, giving rise to autism.

In the associated paper, Vitkup, Iossifov and others use a novel form of analysis called NETBAG (network-based analysis of genetic associations) to identify “the large biological network of genes affected by rare de novo CNVs in autism.” They note that this network is strongly related to genes previously implicated in studies of autism and intellectual disability. And they specify they relate primarily to the development of synapses, the junctions between brain cells which are their transmission nodes; as well as the targeting of axonal fibers and the ability of young neurons to migrate. All are essential aspects of brain development.

Explaining gender skew and apparent female ‘resistance’ to autism
Subsequent sequence-based studies should be able to further resolve individual genes within the CNV regions, and significantly expand the list of candidate genes for autism. Even now, however, the data on spontaneous CNVs and a separate but also an important class of “ultra-rare” CNVs that were inherited by some of the affected children in the sample, reveal interesting and in some cases vexing “asymmetries,” the team reported.

Among these asymmetries: spontaneous causal CNVs were found in 8% of the affected children in the sample; this is four times their rate of occurrence in unaffected siblings. Since CNVs occur with equal frequency across the human population – we all have them, but in most of us the missing or extra genetic material does not hit essential genes or contribute to illness – the fact that they are seen four times as often in affected children as in their unaffected siblings points to their likely contributory role in the illness.

Another striking asymmetry: when spontaneous CNVs contributing to autism were seen in girls, they tended to be much larger and hit many more genes – 15 genes per CNV on average for girls vs. only 2 for boys. This touches on three observed phenomena: the preponderance of boys who become symptomatic; the preponderance of boys who have ASD but are “high-functioning”; and the comparative severity of the illness when it does occur in girls.

Since girls and boys are equally susceptible to DNA damage and new mutation – the rate of new mutation that damages a gene in humans is about one gene per three births – they should each have about the same number of CNVs. Presuming this is the case, why do more boys than girls develop ASD? And why are the observed CNVs in girls larger?

Wigler hypothesizes that females are in some manner “resistant” to autism, and that it takes a much larger, more devastating genomic hit to induce pathology in girls as compared with boys. The cause of this apparent female resistance to comparatively small genetic hits remains one of autism’s mysteries.

It has been speculated that unequal rates of brain development in the sexes may account for the smaller number of females with ASD. Wigler’s team discusses this possibility, noting that females “have an accelerated timescale for a number of cognitive milestones, for example, their first words at an earlier age. A quicker pace of development might reflect a robustness that offers females protection.”

Another mystery concerning gender draws attention to the status of adult women of child-bearing age who might be considered “carriers.” These would be women whose genomes contain transmissible mutations that can cause autism, yet who do not themselves manifest symptoms of ASD. The team speculates that the “high-risk” autism genes they carry may generate other effects in these women. They “may encounter difficulties at later stages of their lives that manifest as a different diagnostic category, or one that reduces fecundity.” If this is true, the disorder is “most likely to be one with a gender bias opposite that of ASD,” such as anorexia nervosa, Wigler proposes.

The team’s next insights about autism genetics will be made possible by a major technological advance – a shift from microarray detection of CNVs to the sequencing of the gene-encoding portions of the genome, or “exome,” of families in the Simons Simplex Collection (which will expand to include 3000 families). This work and work at other institutions of a similar nature should “crack open the field of autism genetics in two years,” says Wigler, whose own team has been gearing up for the sequencing phase during the last year.

Material adapted from Cold Spring Harbor Laboratory.

References
“Rare de novo and transmitted copy number variation in autistic spectrum disorders” will be published June 9 in Neuron. The authors are: Dan Levy, Michael Ronemus, Boris Yamron, Yoon-ha Lee, Anthony Leotta, Jude Kendall, Steven Marks, B. Lakshmi, Deepa Pai, Kenny Ye, Andreas Buja, Abba Krieger, Seungtai Yoon, Jennifer Troge, Linda Rodgers, Ivan Iossifov and Michael Wigler.

“Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses” will be published June 9 in Neuron. The authors are: Sarah R. Gilman, Ivan Iossifov, Dan Levy, Michael Ronemus, Michael Wigler and Dennis Vitkup.

Created in collaboration with the New York Center for Autism, the Institute will be a center of excellence for best-practice evaluations and treatments for individuals living with autism spectrum disorders and other developmental disorders of the brain, across their lifespans. Situated primarily on the Hospital’s 214-acre Westchester Division campus in White Plains, the Institute will be a resource for community-based providers and families; it is scheduled to open in 2012.

Dr. Lord has been at the forefront of research to find ways to better treat autism spectrum disorders. She led the development of tools that have become the gold standard for diagnosis: the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview – Revised (ADI-R). She currently serves as director of the Autism and Communication Disorders Center at the University of Michigan, where she is professor in the Department of Psychology, Psychiatry and Pediatrics, and senior research professor in the Center for Human Growth and Development.

According to the U.S. Centers for Disease Control and Prevention, autism spectrum disorders affect one in 110 children and one in 70 boys. An estimated 1 million to 1.5 million American adults and children live with an autism spectrum disorder.

“With growing numbers of children affected by autism spectrum disorders, there is an ever increasing need for a comprehensive program dedicated to providing the very best in diagnosis and treatment. There is no one better suited to lead this program than Dr. Catherine Lord,” says Dr. Herbert Pardes, president and CEO of NewYork-Presbyterian Hospital. “Her decades-long work of listening and working closely with patients and their families has helped us better understand the unique and complex ways these disorders manifest. And her work to codify and share this knowledge is helping improve the lives of countless individuals and their families.”

Dr. Lord will lead a multidisciplinary clinical team comprising physician-faculty from Weill Cornell Medical College and Columbia University Medical Center in pediatrics, psychology, neurology, psychiatry and other disciplines, as well as specialists in speech and language, occupational and behavioral therapies. Research will extend from the Institute’s clinical services in White Plains to the NewYork-Presbyterian Hospital/Columbia University Medical Center and NewYork-Presbyterian Hospital/Weill Cornell Medical Center campuses in Manhattan.

“We are delighted that this tripartite program, as envisioned by Laura Slatkin, Ilene Lainer and their colleagues, and now to be led by Dr. Cathy Lord, a world expert, will be advancing research and clinical care in autism,” says Dr. Lee Goldman, dean of the faculties of health sciences and medicine at Columbia University Medical Center.

“Collaborative research in the environment of a dedicated clinical program is the ideal way to increase knowledge about these disorders and develop new targeted approaches that best meet the needs of affected children and adults,” says Dr. Antonio M. Gotto Jr., the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College.

“The New York Center for Autism is honored to have Dr. Catherine Lord as director of the Institute for Brain Development,” say co-founders Laura Slatkin and Ilene Lainer. “Dr. Lord is a world-renowned authority on autism. Her deep understanding of the disorder and the field at large will play an important role in advancing the Institute’s work, improving our understanding of the disorder, as well as improving the lives of individuals with autism and their families.”

“I am thrilled to have been chosen to lead the Institute for Brain Development and help shape its development,” says Dr. Lord. “My goal is nothing short of transforming the way autism is treated in the New York metro area and beyond. We intend to provide the very best environment for treating autism spectrum disorder. By integrating our services with community organizations and resources, the Institute will offer a wide variety of options, locations and treatments for families and patients of all ages and needs.”

Dr. Catherine Lord
Throughout her career, Dr. Lord has provided clinical evaluations and consultations and trained university students and professionals in the diagnosis of autism spectrum disorders (ASD). Her current projects include the development of a module for the ADOS appropriate for adolescents and adults with limited verbal skills; analyses of behavioral phenotype data from the Simons Simplex Collection, a repository of cell lines and behavioral measures for families with a child with autism and a typical child; the development of a measure of spontaneous, functional language in children with ASD; several studies of different therapies including for young children and peer-mediated interventions at schools; and a longitudinal study of children followed from age 2 who are now in their 20s.

Dr. Lord graduated with degrees in psychology from UCLA with a B.A., summa cum laude, and a Ph.D. from Harvard University. She received postdoctoral training at the University of North Carolina at Chapel Hill. Prior to joining the faculty at the University of Michigan at Ann Arbor, Dr. Lord has held faculty appointments at the University of Chicago; University of North Carolina, Chapel Hill; University of Alberta School of Medicine, Edmonton, Alberta, Canada; and University of Minnesota, Minneapolis. She was also a visiting professor at the NYU Child Study Center, NYU School of Medicine.

She is the recipient of numerous honors and awards; in 2011 she received the Patricia Buehler Legacy Award for Clinical Innovation from the American College of Occupational Therapy; the Award for Distinguished Scientific Contributions to Clinical Psychology by the Society of Clinical Psychology; and the Asperger/Kanner Medal from the Free University of Berlin. She was chair of the Committee on Effectiveness of Early Intervention in Autism for the National Research Council and is currently on the DSM V Neurodevelopmental Disorders Committee. She has given more than 100 invited lectures and authored more than 160 original, peer-reviewed papers, nine books and more than 60 reviews and book chapters.

Material adapted from NewYork-Presbyterian Hospital/Columbia University Medical Center and NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

Identifying children with ASD as young as possible is critical for the early intervention that can improve their lives and ability to function in the world. But a systematic way to do that has not been established, according to the lead author of the study published May 1, 2011, in Pediatrics, Judith S. Miller, Ph.D., formerly of the U Department of Psychiatry and now at the Children’s Hospital of Philadelphia.

The study was designed to see if a partnership between pediatricians and autism experts could identify at-risk children in a real-life, clinical setting, and captured a diverse range of race and ethnicity, including Hispanic, Pacific Islander, black, and Native American toddlers. Ultimately, the study identified 10 toddlers with early signs of ASD that had not yet been identified.

“There has been limited research into how screening might occur in a real-life situation,” Miller said. “Our study demonstrated how collaboration between pediatricians and autism experts facilitates screening.”

She and her U colleagues used two widely accepted questionnaires to screen 796 tots between 14 and 24 months at Granger Pediatrics, a large Salt Lake Valley medical practice. The questionnaires – a 23-item checklist for parents called the Modified Checklist for Autism in Toddlers (M-CHAT), and the Infant Toddler Checklist (ITC), a 24-item broad-based screener of language and communication – were given during a six-month period in 2008. They were filled out by caregivers (usually parents) and pediatricians for each child during all types of patient visits – well-child, follow-up, sick visits, and immunizations.

Early signs of ASD include impairments in social attention, such as the inability to direct the attention of others or to respond to other people easily and naturally; impaired nonverbal communication; lack of integration of verbal, facial, and gestural communication; lack of response to name; impairments in the ability to imitate; and repetitive use of objects. With this in mind, the questionnaires asked caregivers and providers to answer questions such as: When you say your child’s name, does he or she respond? Does your child pick up objects and give them to you? Does your child imitate and pretend to use objects? Does your child try to attract your attention to his/her activities?

Toddlers who exhibited three or more inappropriate behaviors on the 23-item M-CHAT were identified as potentially at-risk for ASD. The ITC assessment was compared to a norm score.

Miller and her colleagues evaluated each questionnaire and if either the M-CHAT or ITC indicated a child had signs of ASD, the researchers then conducted a follow-up interview on the phone to verify the parent’s responses. If the follow-up interview verified the potential signs of autism, the child was evaluated in person.

Through the combination of using both screening tests for each child, Miller and her U colleagues identified 13 children with early signs of ASD, 10 of whom had not previously been evaluated for ASD Neither questionnaire identified all 10 children, and two children were initially missed by both questionnaires. But the act of filling out the screeners made parents reconsider their child’s development, which ultimately led to an evaluation.

In 2007 the American Academy of Pediatrics (AAP) recommended that all children be screened for autism at 18 and 24 months of age. “This study validates those recommendations” says co-investigator Paul Carbone, M.D., who is a member of the AAP Autism Subcommittee and an assistant professor of pediatrics at the University of Utah. According to Carbone, many toddlers are still not being screened because implementing autism screening into pediatric offices presents challenges. “This is why we offered to partner with pediatricians to help address some of those challenges.” he says.

The study not only showed that a partnership between autism experts and providers can identify at-risk children at a much younger age, but also provided immediate help to 10 toddlers who may have otherwise been missed for several years – critical lost time for intervention.”It was great to help parents see their child’s strengths as well as areas of concern, and to try to help them access intervention before the signs of ASD had become severe.” Miller said. “I hope it leads to a better outcome.”

The partnership with Granger Pediatrics was critical. “The faculty and staff were incredibly supportive and together we accomplished something other research groups haven’t,” Miller said. “We couldn’t have done this without them.”

For future research, Miller suggests an even larger study in a larger set of pediatric practices to determine the costs of widespread screening and study the impact of screening on families and toddlers with ASD. Co-authors on the study were: Terisa Gabrielsen, Michele Villalobos, Ph.D., Rebecca Alleman, Natalie Wahmhoff, Paul S. Carbone, M.D., assistant professor of pediatrics at the U medical school, and Brandon Segura.

Material adapted from University of Utah Health Sciences.

The game works in a similar way to popular musical titles like Guitar Hero: different colored shapes appear on screen, prompting the child to press a matching key.

Each of the different shapes plays a different chord, and when the right buttons are pressed a flower grows on the screen. The calming music and the positive reinforcement of showing success on screen is designed to be enjoyable and help autistic children develop independent learning skills.

Game art screen in the University of Abertay Dundee game for children with autism.

John said, “I really wanted to use the creative skills I learnt at Abertay University to help children with learning difficulties, and giving them the opportunity to use music to learn and relax at any time felt like a really important thing to do.

“There’s very little available in terms of interactive games for children with autism, which is a huge shame. By bringing together shape and color learning with relaxing music and interactive play, I hope this project can make a real difference.

“Even though this is the end of my degree, I don’t see the project ending at all. There’s so much more work to do, from testing and developing the game further to finding a company to work with to build a prototype controller. This is just the start.”

Gameplay screenshot from University of Abertay Dundee game for children with Autism.

John’s Mother worked with children with special educational needs, which inspired John to put his creative skills to a practical, beneficial use.

The project has been developed with the invaluable support of Seonaid Birse and Maggie Powell, music teachers at Kingspark School in Dundee, a dedicated school for children with learning difficulties.

Seonaid said, “The combination of the visual impact and the use of sound is very effective for working with children with autism. There’s a sense of control for the pupil, which they may find difficult to achieve in a normal learning environment.

“The positive reward of seeing the flower grow when the right keys are pressed is also very important, helping make learning a positive experience for children who may have complex needs and be unable to communicate verbally.”

Maggie added, “John’s game really promotes positive learning and a sense of progression for children on the autistic spectrum. It’s also great that the game could be used at home or in the classroom.

Menu screen from the University of Abertay Dundee game for children with autism.

“These children face so many limitations in their lives. This project actually opens up their world to many more possibilities and it has huge potential for development in many, many ways.”

John is now working with the school to develop his game further, and is looking to work with a commercial partner to expand the game and build a dedicated controller.

This game is just one of the projects on show at the Abertay Digital Graduate Show, which this year features more students and more courses than ever before.

For those who live in Europe, the show is open to the public Monday to Friday, 9.30am-5pm, until 3rd June in Abertay University’s main Kydd Building and on the top floor of the Student Centre. John’s game is on show on the top floor of the Student Centre.

Material adapted from University of Abertay Dundee.

The discovery also identifies a new line of attack for researchers, who currently face a vast array of potential fronts for tackling the neurological disease and identifying its diverse causes.

“If you randomly pick 20 people with autism, the cause of each person’s disease will be unique,” said principal investigator Dr. Daniel Geschwind, the Gordon and Virginia MacDonald Distinguished Chair in Human Genetics and a professor of neurology and psychiatry at the David Geffen School of Medicine at UCLA. “Yet when we examined how genes and proteins interact in autistic people’s brains, we saw well-defined shared patterns. This common thread could hold the key to pinpointing the disorder’s origins.”

The research team, led by Geschwind, included scientists from the University of Toronto and King’s College London. They compared brain tissue samples obtained after death from 19 autism patients and 17 healthy volunteers. After profiling three brain areas previously linked to autism, the group zeroed in on the cerebral cortex, the most evolved part of the human brain.

UCLA scientists measured the expression levels of more than 20,000 genes in tissue samples from autistic and healthy brains. When the samples were grouped by expression patterns, most autistic brains (red bar at top, left) showed a striking overlap.

“We were surprised to see similar gene expression patterns in most of the autistic brains we studied,” said first author Irina Voineagu, a UCLA postdoctoral fellow in neurology. “From a molecular perspective, half of these brains shared a common genetic signature. Given autism’s numerous causes, this was an unexpected and exciting finding.”

The researchers’ next step was to identify the common patterns. To do this, they looked at the cerebral cortex’s frontal lobe, which plays a role in judgment, creativity, emotions and speech, and at its temporal lobes, which regulate hearing, language, and the processing and interpreting of sounds.

When the scientists compared the frontal and temporal lobes in the healthy brains, they saw that more than 500 genes were expressed at different levels in the two regions.

In the autistic brains, these differences were virtually non-existent.

“In a healthy brain, hundreds of genes behave differently from region to region, and the frontal and temporal lobes are easy to tell apart,” Geschwind said. “We didn’t see this in the autistic brain. Instead, the frontal lobe closely resembles the temporal lobe. Most of the features that normally distinguish the two regions had disappeared.”

Two other clear-cut patterns emerged when the scientists compared the autistic and healthy brains. First, the autistic brain showed a drop in the levels of genes responsible for neuron function and communication. Second, the autistic brain displayed a jump in the levels of genes involved in immune function and inflammatory response.

“Several of the genes that cropped up in these shared patterns were previously linked to autism,” said Geschwind. “By demonstrating that this pathology is passed from the genes to the RNA to the cellular proteins, we provide evidence that the common molecular changes in neuron function and communication are a cause, not an effect, of the disease.”

The next step will be for the research team to expand its search for the genetic and related causes of autism to other regions of the brain.

Autism is a complex brain disorder that strikes in early childhood. The disease disrupts a child’s ability to communicate and develop social relationships and is often accompanied by acute behavioral challenges. In the United States, autism spectrum disorders are diagnosed in one in 110 children — and one in 70 boys. Diagnoses have expanded tenfold in the last decade.

The study was funded by the National Institute of Mental Health, the Canadian Institutes of Health Research, and Genome Canada. Tissue samples were provided by the Autism Tissue Project, the Harvard Brain Bank and the Medical Research Council’s London Brain Bank for Neurodegenerative Disease.

Geschwind’s and Voineagu’s co-authors included Jennifer Lowe, Yuan Tian, Steve Horvath, Jonathan Mill and Rita Cantor of UCLA; Benjamin Blencowe and Xinchen Wang of the University of Toronto; and Patrick Johnston of King’s College London.

Material adapted from University of California, Los Angeles (UCLA), Health Sciences.

“Mothers of children with autism were significantly less likely than those of typically developing children to report having taken prenatal vitamins during the three months before and the first month of pregnancy,” said Rebecca J. Schmidt, assistant professor in the Department of Public Health Sciences in the UC Davis School of Medicine and the study’s lead author.

The finding was “strong and robust,” the study authors said, and is the first to suggest a concrete step women can take that may reduce the risk of having a child with autism. The study, “Prenatal vitamins, functional one-carbon metabolism gene variants, and risk for autism in the CHARGE Study,” is published online today on the website of the Journal of Epidemiology. It is scheduled to appear in print in July.

Consuming prenatal vitamins may be especially effective for genetically susceptible mothers and their children. For women with a particular high-risk genetic make up who reported not taking prenatal vitamins, the estimated risk of having a child with autism was as much as seven times greater than in women who did report taking prenatal vitamins and who had more favorable gene variants, the study found.

The authors postulate that folic acid, the synthetic form of folate or vitamin B9, and the other B vitamins in prenatal supplements, likely protect against deficits in early fetal brain development. Folate is known to be critical to neurodevelopment and studies have found that supplemental folic acid has the potential to prevent up to 70 percent of neural tube defects, the authors said.

“This finding appears to be the first example of gene-environment interaction in autism,” said Irva Hertz-Picciotto, professor and chief of the division of environmental and occupational health in the Department of Public Health Sciences in the UC Davis School of Medicine.

“It is widely accepted that autism spectrum disorders are the result of multiple factors, that it would be extremely rare to find someone who had a single cause for this behavioral syndrome. Nevertheless, previous work on genes has generally ignored the possibility that genes may act in concert with environmental exposures,” said Hertz-Picciotto, the study’s senior author and a researcher affiliated with the UC Davis MIND Institute.

To conduct the study, researchers collected data from approximately 700 Northern California families with 2- to 5-year-old children who had autism or typical development and were participants in the Childhood Autism Risk from Genetics and the Environment (CHARGE) study between from January 2003 to December 2009. All children were born in California and came from families that spoke either English or Spanish. The autism diagnoses were confirmed through testing at the UC Davis MIND Institute.

Women who participated in the CHARGE study were asked via telephone whether they took prenatal vitamins, multivitamins, or other supplements at any time during the three months prior to and during their pregnancies and during breastfeeding. If the respondent said she had taken vitamins, she was further asked what type she took, at what dosage and frequency and during which months of pregnancy she consumed them.

“Because the mothers were asked about their vitamin use years after their pregnancies and after their child’s developmental status was known, some error is expected in their reporting. Moreover, in comparison with mothers who have an affected child, mothers whose children are healthy and show typical developmental milestones may be less likely to remember accurately, simply because they have less reason to reflect on and be concerned about their behaviors years earlier,” Schmidt said. This could have biased the results, she pointed out. Further research will be needed to rule out reporting bias.

The researchers accounted for maternal education and the year the child was born; results were the same when also accounting for the mother’s age. However, after the first month of pregnancy, there was no difference between mothers who did and did not take prenatal vitamins. This indicates that, by the time most women are aware that they are pregnant, taking prenatal supplements may not benefit the child in terms of risk for autism.

Significant interaction effects were observed for two maternal genes, including a well-studied variant on the methylenetetrahydrofolate reductase (MTHFR) gene associated with less efficient folate metabolism and increased levels of homocysteine, an amino acid.

Mothers of children with autism were 4.5 times more likely to both have the less efficient MTHFR 677 TT genotype and to report not taking prenatal vitamins during the period around conception than were mothers of typically developing children.

The other maternal gene variant with a significant interaction leads to decreased cystathionine-beta-synthase (CBS) activity and elevated plasma homocysteine. Increased risk for autism was also associated with other maternal gene variants associated with less efficient one-carbon metabolism, but only if the mother reported not taking the prenatal vitamins in those early months before and right after conception.

In addition, being homozygous for a common, functional variant in the child’s catechol-O-methyltransferase (COMT) gene was associated with more than seven times the estimated risk for autism in mothers who reported not taking the supplements around the time of conception, compared to children with other genotypes whose mothers did report periconceptional prenatal vitamin intake.

This gene reduces COMT enzyme activity three- to four-fold. The COMT enzyme, well known for its role in dopamine degradation, is activated during early neurodevelopment. Structural and functional brain differences have been described across COMT genotypes, particularly in the hippocampal and prefrontal cortex, regions affected by autism.

The finding, if replicated, provides a potential means of reducing the risk of having a child with autism. the authors said.

“The good news is that if this finding is replicated, it will provide an inexpensive, relatively simple evidence-based action that women can take to reduce risks for their child, which is to take prenatal vitamins as early as possible in a pregnancy and even when planning for pregnancy,” Hertz-Picciotto said.

Other study authors include Robin L. Hansen, Linda C. Schmidt and Daniel Tancredi, all of UC Davis, and Jaana Hartiala and Hooman Allayee, of UCLA.

Material adapted from UC Davis Health System.

The report concludes the first phase of a four-year project to analyze the comparative efficacy of preschool programs for children with ASD. It involves developing and validating assessment measures to demonstrate that the classrooms in the study are actually implementing the teaching models at high levels of adherence.

The researchers found that the assessment instruments they developed accurately measured how well the models were executed in the classrooms and that these measurements were able to discriminate between diverse teaching approaches. The goal is for these tools to provide an evaluation method for intervention programs for children with autism, all over the country, explains Michael Alessandri, clinical professor of Psychology, in the College of Arts and Sciences, executive director of UM/Nova Southeastern University Center for Autism and Related Disabilities, (UM-NSU CARD), director of the Division of Community Outreach and Development at UM and principal investigator for the UM component of the project.

“This is an important first step. We hope that the utilization of these kinds of fidelity tools will enable schools to more closely monitor the degree to which intervention methods are being delivered, relative to what the model intends,” he said. “If these useful methods are adopted, parents will have a way to assess the quality of their child’s treatment.”

The scientists looked at two comprehensive programs for autistic children in preschool: the Treatment and Education of Autistic and Communication Handicapped Children (TEACCH) and the Learning Experiences and Alternative Programs for Preschoolers and Their Parents (LEAP). The two models were chosen because they are well established and widely used in public school systems in the U.S.

The study took place in 34 classrooms, during four months of the school year. A maximum of four observations were made in each class. The findings may help explain differences in children’s responses to different intervention treatments, explains Anibal Gutierrez, assistant scientist of UM-NSU CARD and co-author of the study.

“If we can ensure that the different programs are all good programs, implemented at a high level of fidelity, then we may be able to attribute differences in outcomes to individual child differences,” said Gutierrez. “We could explain why children with a particular profile may benefit from one program over another.”

Understanding how closely an intervention model adheres to its intended plan may also help to scale up programs within the broader community, explains Drew Coman, Ph.D. student in the Department of Psychology at UM and co-author of the study.

“I believe these measure not only provide a brief guide to implement one of these treatment programs, but they also provide a way to see the strengths of a particular classroom as well as identify the features that may need a bit more support and improvement,” said Coman. “Ultimately, these measures provide a means to conduct such evaluations, and will hopefully lead to more support for teachers, better classrooms, and ideally improved student outcomes for students with ASD.”

Material adapted from University of Miami.

Reference
The study is titled “Assessing implementation of comprehensive treatment models for young children with ASD: Reliability and validity of two measures.” The principal investigator is Samuel Odom, director of the Frank Porter Graham Child (FPG) Development Institute and professor of the School of Education, at the University of North Carolina (UNC). The co-principal Investigator is Brian Boyd, assistant professor in the Division of Occupational Science and Occupational Therapy, UNC. The lead author is Kara Hume, investigator in the FPG Development Institute, UNC. Co-authors are Matt McBee, investigator and statistician in the FPG Development Institute, UNC and Evelyn Shaw, educational planner/consultant in the FPG Development Institute, UNC and Laurie Sperry, Assistant Research Professor in the School of Education and Human Development, at the University of Colorado. The study was funded by U.S. Department of Education Institute Of Education Sciences.

With funding from the American Recovery and Reinvestiment Act, Dr. Brian O'Roak came to the University of Washington in Seattle to study genetic mutations in autism spectrum disorders. (Credit - Clare McClean)

O’Roak and colleagues analyzed the exomes of 20 individuals with autism spectrum disorder and their parents, an approach called trio-based exome sequencing. Autism spectrum disorders encompass a range of social impairments in language, communicating and interacting with others, repetitive behaviors, and engrossing fascinations. The condition can be mildly to severely disabling.

The researchers found 21 newly occurring mutations, 11 of which altered proteins. Proteins altered by genetic mutations may hold clues to the biological pathways involved in the development of the disease. The abnormal proteins or the pathways they affect could draw interest as targets in the design of preventive or treatment drugs.

At a University of Washington lab where they study the genetics of autism spectrum disorders are Drs. Brian O'Roak, Evan Eichler (seated) and Jay Shendure (right) of the Department of Genome Sciences. Eichler is an investigator in the Howard Hughes Medical Institute. (Credit - Clare McLean)

In four of the 20 families studied, O’Roak and colleagues identified disruptive new mutations that are potentially causative for autism. In examining the clinical data on the child in each of the four families, they learned that these children were among the most severely affected of the study group, both in intellectual disability and in their autistic features.

These initial findings point to the possibility that these new sporadic disruptive genetic mutations could contribute substantially to the underlying mechanisms and severity of autism in perhaps 20 percent of the cases in which no larger family history of autism exists. In some cases, the combination of newly appearing mutations and those inherited from the parents may worsen the severity of the disorder.

“The results of the study suggest a multi-hit model as a trend, but this possibility would need to be further explored by comparing a much larger number of affected and unaffected siblings,” said Eichler.

In this study, many of the discovered mutations were located in genome areas that were highly conserved during evolution. These parts of the genome likely play a fundamental role in the biology of many animals, including humans. Mutations in these regions tend to have significant repercussions.

“Consistent with the complexity of autism and its symptoms, the new mutations were identified in several different genes,” lead author O’Roak said. Moreover, many of these mutated genes have already been associated with other brain disorders, including epilepsy, schizophrenia and intellectual disability – reflecting a surprising genetic overlap.

Drs. Brian O'Roak and Evan Eichler study the genetics of autism spectrum disorders in a genome science lab at the University of Washington. (Credit - Clare McLean)

How and why sporadic mutations such as these originate is as yet unknown. However researchers are uncovering clues about risk factors.

In six of the affected children in this study, the scientists were able to trace the original genes that were later mutated in the child back to the father’s half the child’s genome, and in one case to the mother’s half.

These genetic findings further support population studies showing that autism is more common among children of older parents, especially older fathers. Eichler explained that certain genetic mutations might more likely occur during sperm formation as men age.

The scientists wrote, “The identification of de novo events along with disruptive inherited mutations underlying sporadic cases of autism spectrum disorders has the potential to fundamentally transform our understanding of the genetic basis of autism.”

“Our results,” Shendure noted, “show that trio-based exome sequencing is a powerful approach for identifying new candidate genes for autism spectrum disorders.”

From identifying mutations, researchers hope to learn more about the biology of autism and to understand interacting genetic and environmental factors within the context of families with affected and unaffected members.

In addition to O’Roak, Shendure and Eichler, other researchers on the study included Pelagia Deriziotis from the Wellcome Trust Centre for Human Genetics, University of Oxford, United Kingdom; Choli Lee, Laura Vives, Jerrod J. Schwartz, Santosh Girirajan, Emre Karakoc, Alexandra P. MacKenzie, Sarah B. Ng, Carl Baker, Mark J. Rieder, Deborah A. Nickerson, all from the UW Department of Genome Sciences in Seattle; Raphael Bernier of the UW Department of Psychiatry and Behavioral Sciences; and Simon E. Fisher of the Wellcome Trust Centre for Human Genetics and the Language and Genetics Department of the Max Planck Institute for Psycholinguistics, Nijmegen, Netherlands.

Material adapted from University of Washington.

“It’s incredibly important that we find the most effective interventions for children with autism spectrum disorders,” said Susan Hyman, M.D., chief of Neurodevelopmental and Behavioral Pediatrics at URMC’s Golisano Children’s Hospital and an active autism researcher and clinician. “We also need to examine whether traditional and non-traditional treatments may be helping or causing harm, and what roles environmental factors may be playing in autism.”

Hyman said that participation in the Autism Treatment Network (ATN) funded by Autism Speaks and the Health Resources and Services Administration (HRSA) and partnering with the Clinical and Translational Science Institute (CTSI) has allowed the growth of clinical research related to autism at URMC. The abstracts presented this week reflect Rochester data and analyses of the ATN database of more than 3,000 children and youth across 15 ATN sites in the U.S. and Canada.

Autism and nutrition
Patricia Stewart, Ph.D., R.D., director of Bionutrition for the CTSI at URMC, examined the nutritional intake of children with autism, including supplement use. It is important to understand how the significant food related behaviors and aversions that children with autism impact their current and future health. Her abstract shows that two-thirds of children with autism are taking supplements, twice the rate in the general pediatric population (32 percent). She reports that the nutrients most likely to be deficient in the children were not included in adequate amounts in the supplements used. For example, most of those supplements contain vitamin D (97 percent), but few contain choline (37 percent), vitamin K (11 percent) and potassium (8 percent). None contained any fiber, which is important for bowel health and is eaten in limited amounts by picky eaters.

In addition, there were several nutrients in supplements – folate, niacin, and vitamin A – that exceeded recommended levels even before adding in the nutrients from food. Excessive amounts of these nutrients do not usually cause a problem, but there are known side effects that families and their health care providers need to be aware of. Too much folate can mask a neurological complication of vitamin B12 deficiency and some evidence shows that high levels can provoke seizures in patients on anti-convulsant medications. Too much niacin can cause flushing, gastrointestinal distress, and liver damage. And too much vitamin A can have teratological effects (birth defects and other abnormalities of development), liver toxicity, reduced bone mineral density resulting in osteoporosis, and central nervous system disorders.

“It’s important for dieticians and health care providers to know the potential nutritional insufficiencies and excesses children with autism may be experiencing,” Stewart said. “Diet and supplement use can impact their health and some nutritional problems may also affect their behavior. There is a great need for additional research in this area.”

Food dyes and sleep
Many families – who have children with autism or Attention Deficit Hyperactivity Disorder (ADHD) or who have typically developing kids – eliminate food dyes from their diet hoping to avoid behavior issues. Some studies suggest artificial food dyes may increase hyperactivity in children, but the effect on children with autism has not been examined. Hyman, Stewart and their collaborators, in the course of conducting a study of the diet and nutrition of children with autism spectrum disorders, performed a pilot study on the effect of food dye consumption on a small group of children with autism. Food dye intake was determined from a three-day food record and examined relative to parent questionnaires regarding behavior.

Among the 25 children enrolled, five had no food dye in their diet. Hyman found no correlation between artificial food dye consumption and repetitive behaviors or externalizing behaviors; however, she did find a correlation between yellow food dye consumption and sleep disturbances.

“While this is only a pilot study and needs to be interpreted conservatively, it merits a clinical trial to determine whether food dye might aggravate behaviors in children with ASD who are at greater risk for sleep problems than other children,” Hyman said.

Complementary treatments
Another abstract authored by Hyman and colleagues was based on an analysis of the national dataset collected by the Autism Treatment Network on the use of complementary and alternative medicine in children with autism. It highlights the need for physicians to keep track of what other treatments parents may be using for their children. About 450 of the almost 2,500 children in the registry at the time the data were analyzed reported use of complementary therapies. About one-fifth of these 450 children were given a special diet at the time they entered the Autism Treatment Network. However, that rate changed throughout the first year of follow up. Between 5 and 10 percent of families who were followed over the next year stopped using a special diet and about the same number started diets over the next year.

“Many children with autism are put on special diets by their families to see if elimination of specific foods such as those containing gluten or casein will help with development or behavior. Health care providers need to ask about the use of dietary interventions so appropriate nutritional counseling can take place in the context of primary and specialty care,” Hyman said. “When it comes to complementary therapies, doctors do need to ask and families do need to tell.”

Material adapted from University of Rochester Medical Center.

“Basically, the way that you communicate or approach a person with autism has to be significantly different than from traditional styles,” Migyanka said. “Persons with autism tend to be very sensitive to sensory stimuli and often have difficulty understanding directions and commands so it is important that emergency responders communicate with them in a different way than protocols usually dictate.”

Migyanka and Glor-Scheib (Department of Special Education and Clinical Services), along with Fratangeli (Department of Communications Media), worked through the Office of Special Projects in the College of Education and Educational Technology to develop the training module.

The module consisted of a training DVD featuring parents, professionals, and first responders engaged in emergency situations. Additionally, training participants are provided a manual that expands on the information portrayed in the DVD. Finally, participants are given an evaluation of the content in the DVD and the manual.

This training module has been designated to go on the Department of Health Learning Management System in order for the training to reach as many first responders as possible, and allow the participants to gain continuing education credits.

Material adapted from Indiana University of Pennsylvania.

Scientists at IMFAR will discuss and disseminate the latest scientific findings focused on the nature, causes, and treatment options for autism spectrum disorders. By bringing together both clinicians and research scientists, IMFAR provides a unique opportunity to foster international dialogue across various disciplines and methods.

This year’s meeting includes more than 900 research and educational presentations, lectures, and panel discussions over three days.

“This IMFAR, our 10th anniversary meeting, will showcase some of the most rigorous and exciting science presented at any IMFAR meeting. Studies dealing with topics ranging from genetics to environmental factors, from medical co-morbidities to early intervention will be presented during the three-day meeting,” said David G. Amaral, Ph.D. President of INSAR and Research Director for the UC Davis M.I.N.D. Institute. “It is exciting that a great many of the participants are students who are immersing themselves in the collaborative, interdisciplinary science that will undoubtedly lead to understanding, prevention, and more effective treatments of autism spectrum disorders”

A press conference will be held one day before the start of the conference on Wednesday May 11 at 11 a.m. PT at the Manchester Grand Hyatt. At the press conference, scientists will discuss key studies to be presented during IMFAR including how autism affects parental employment and earnings; the first study of long-distance connections in the autistic brain in the first years of life when the behavioral symptoms begin; the potential role of prenatal conditions on autism including maternal diabetes, flu and fever, and cesarean birth; and a double-blind trial of N-Acetylcysteine in children to determine its effect on behavioral deficits; and the behavioral and health profile of autism in later life.

Press Conference participants will include:

• David Amaral, Ph.D., President, the International Society for Autism Research
• Eric Courchesne, Ph.D., UCSD
• Antonio Hardan, M.D., Stanford University School of Medicine
• David Mandell, Sc.D., Chairman of IMFAR Program Committee
• Irva Hertz-Picciotto, Ph.D., UC Davis
• Marsha Malick Seltzer, Ph.D., Weisman Center, University of Wisconsin

Additional Resources
Additional information for this event, including registration, can be found here.

For a free program/brochure of this event, go here.

Material adapted from Autism Speaks.

The study “Prevalence of Autism Spectrum Disorder in a Total Population Sample,” scheduled to be published online on May 9 in the American Journal of Psychiatry, reports on autism among approximately 55,000 children ages 7 to 12 years in a South Korean community. These children include those enrolled in special education services and a disability registry, as well as children enrolled in general education schools.

“While this study does not suggest that Korean children have more autism than other populations or that a more accurate rate for the U.S. is closer to 2.64 percent, it does suggest that autism may be more common than previously thought,” said Roy Richard Grinker, GW professor of anthropology and international affairs and member of the study’s research team. “This research powerfully demonstrates that the methods one uses to study prevalence will profoundly influence the estimate,” said Professor Grinker, author of Unstrange Minds: Remapping the World of Autism.

Under the leadership of Yale psychiatrist and epidemiologist Young-Shin Kim, all children were screened with surveys distributed to both parents and teachers, and then evaluated using comprehensive diagnostic assessments. Unlike the studies carried out by the Centers for Disease Control and Prevention (CDC), which analyzed records and registries, the researchers attempted to look at each child in every school, even those who did not have a record of any special education need. This method unmasked cases that could have gone unnoticed to epidemiologists relying on a records-based approach.

“This study is further evidence that autism transcends cultural, geographic, and ethnic boundaries and that autism is a major global public health concern, not limited to the Western world,” said Autism Speaks Chief Science Officer Geraldine Dawson. “Notwithstanding the need for replication, this study also provides important evidence that the application of validated, reliable and commonly accepted screening procedures and diagnostic criteria applied to a total population has the potential to yield an ASD prevalence exceeding previous estimates.”

To date, researchers have not found a difference in the way ASD is expressed in children around the world, but certain cultural factors may affect diagnostic practices and prevalence estimates. Therefore, this study took a comprehensive and anthropological approach to mitigate potential cultural bias. Parent and teacher focus groups were conducted to identify local beliefs that might influence symptom reporting and other misunderstandings. Additionally, the diagnostic tools were also translated, back-translated, and validated for Korean children and only best-estimate clinical diagnoses were reported. Furthermore, each diagnostic team was composed of Korean diagnosticians with extensive clinical and research experience in both the U.S. and Korea and a random sample of diagnoses was validated by North American experts.

The team considered that more Korean children with ASD may be found in mainstream education settings based on the design of the Korean educational system. In these settings, instruction is highly structured with significant behavioral regulation across a longer school day – often more than 12 hours long with 5-6 days of instruction each week and extracurricular academic tutoring at off-site academic institutes. This structure may help children with ASD to function at various levels in the Korean general population while not receiving special education services.

The researchers highlighted that appropriate translation and adaptation of the gold-standard assessment methods used in the U.S. and other English-speaking countries can reliably diagnose autism in other languages and cultures.

This research was primarily funded by a pilot research grant from Autism Speaks with additional funding from the Institute for Ethnographic Research, part of GW’s Columbian College of Arts and Sciences. In addition to this study, Autism Speaks is supporting similar efforts epidemiological research efforts in India, South Africa and Taiwan.

Material adapted from George Washington University.

The top prize is awarded to Greg Katz and Tom Rim, both from University of Illinois College of Fine and Applied Arts Industrial Design, Urbana-Champaign, Chicago, Illinois, for Gobug. Second place, for weSYNC was awarded to Noel Cunningham and the third place prize for Visual Watch was awarded to Cameron Zotter, both from the Maryland Institute College of Art (MICA) in Baltimore, Maryland.

“These innovations in technology are examples of the next frontier in finding solutions to improve daily life for individuals with autism,” stated Autism Speaks Chief Science Officer Geraldine Dawson, PhD., “These students from over 30 countries around the world represent the next generation of designers and innovators who will think creatively on how to apply technology to autism.”

The Gobug is an interactive toy designed to facilitate an inclusive social learning experience for children with Autism Spectrum Disorder. Individuals of all ages and abilities are welcome to join, play, and learn. Gobug is operated through the combined direction of multiple active controllers and the more in sync the controllers are, in the same pointed direction, the faster Gobug moves.

“The Autism Connects Competition provided us a challenge that was truly purpose driven,” stated Gobug’s winning co-designer Greg Katz. “There’s meaning to something like this. It’s a purpose that you feel in your heart. There are so many incredible individuals with ASD. We only hope that our concept work (Gobug) can make a positive difference in someone’s life.”

Tom Rim, who also co-designed Gobug added, “During the ‘Autism Connects’ competition, we realized that this is a global effort. It requires people from all over to contribute and do their part. It’s important that students like us understand that design is more than just about making something look sleek or fashionable. Design is about providing the user with an enhancing experience. In this case, the user is an individual that deserves every bit as much attention as next.”

weSYNC helps children with Autism Spectrum Disorder who have rigid schedules to work with different therapists, doctors, and educators on a daily basis. An application for the iPad, iPhone, and Web, weSYNC creates a specialized profile for the individual with ASD, gathers knowledge from each caregiver and establishes a centralized location where it can be accessed and edited by everyone. Establishing a dialogue among doctors, therapists, teachers and parents allows them to share information and reinforce one another’s efforts.

Visual Watch is a time management and picture exchange communication system (PECS) tool designed specifically for people with ASD which addresses both time management and the need for a more mobile PECS communication system. This device to be worn on a wrist replaces a bulky notebook of PECS picture cards and new communication pictures can be uploaded to the watch for the user to develop an extensive vocabulary.

Allan Chochinov, partner of Core77, the New York-based design network serving a global community of designers and design enthusiasts who co-sponsored the competition, remarked on the breadth of the submissions, “We were incredibly impressed with the wide diversity of solutions, and with the overall rigor of the designers’ efforts. From individuals to group submissions, it was evident that the participants took the subject very seriously, applied diligence to their design responses, and demonstrated the unique power of design to re-imagine possibilities. We are proud to have produced this competition, and are extremely grateful to our community of designers for their passion and commitment.”

These top juried student innovators will travel to the International Meeting for Autism Research (IMFAR) in San Diego May 12-14 to attend sessions with over 1900 scientists and autism advocates from countries around the world, and present their design concepts at the annual IMFAR Technology Demonstration session sponsored by Autism Speaks. These top three prizes were selected from a field of 126 submissions in this first-ever “Autism Connects” competition, selected by a panel of judges including renowned advocates and authors Temple Grandin and John Elder Robison; Yves Béhar, the founder of the San Francisco and New York-based integrated design agency fuseproject; Lisa Strausfeld, partner in Pentagram, the distinguished international design consultancy; Richard Seymour, co-founder of internationally renowned design and innovation company Seymourpowell; developmental and clinical psychologist Peter Mundy, Ph.D.; the nationally recognized entrepreneur Dan Feshbach; Dr. Peter Gerhardt, Director of Education – Upper School for the McCarton School in New York City; Autism Speaks Vice President of Scientific Affairs Andy Shih, Ph.D., and Professor in the Department of Educational and Counseling Psychology and Special Education, and Director of the Centre for Interdisciplinary Research and Collaboration in Autism (CIRCA) at the University of British Columbia, Pat Mirenda.

Autism Connects judge Temple Grandin reflected on how she personally could have benefited from technology, “Technology can be very useful. iPads and other tablet computers would be easy for people with autism to type on and are affordable and portable. It would have been very useful for me to have a program where I could look at videos of many different REAL people showing various facial expressions. They must be videos of real people and not cartoons. I need to be able to see what each facial expression looks like on MANY videos of different real people such as men, women, and children.”

The online competition was run by creative technology platform company jovoto who organized a separate judging by an online community of professionals, advocates and students. Six concepts were selected as Community Prize winners, including Gobug from Greg Katz and Tom Rim, again in first place; second community favorite Communicating through Music by Cande Mosse from FADU (Facultad de Arquitectura, Diseño y Urbanismo) at UBA (Universidad de Buenos Aires) Industrial Design; third and fourth community favorites Visual Watch and Line-up Facial Recognition Game from Cameron Zotter, from the Maryland Institute College of Art Graphic Design MFA in Baltimore MD; weSYNC was the fifth community favorite by Noel Cunningham a first year graduate student from the Maryland Institute College of Art (MICA); and Bearhug by Lisa Fraser from the Emily Carr University of Art + Design in British Columbia.

Material adapted from Autism Speaks.

Now, scientists have further characterized a mouse model that provides some insights into biological factors related to social deficits by comparing mice that had their oxytocin receptor gene made inactive, using a specialized technique called genetic knockout, with unaltered mice.

The knockout mice (OTR^-/-) displayed impaired social behavior, increased aggression, and reduced cognitive flexibility leading to resistance to change. These behaviors returned to normal when the OTR^-/-mice were given oxytocin or vasopressin treatment.

“These findings confirm and highlight the importance of oxytocin for social behaviors. This animal model also may be useful  in evaluating the effectiveness of drugs, including vasopressin agonists, that may help improve social behavior in autism, schizophrenia, and other disorders” said Dr. John Krystal, Editor of Biological Psychiatry, the journal publishing these results.

“While no animal model can be expected to replicate the full complexity of the human behavioral autistic phenotype, the OTR^-/- mouse may really help to understand the co-occurrence of these symptoms as a syndrome,” explained Dr. Bice Chini, author and senior researcher of CNR – Institute of Neuroscience, Milano.

One important goal now is to fully characterize the neurodevelopmental processes modulated by oxytocin and vasopressin in order to fully understand their ability to reverse autistic symptoms.

Material adapted from CNR-Consiglio Nazionale delle Ricerche.

Among the children included in the study, those conceived during winter had a significantly greater risk of autism, the study found. The risk of having a child with an autism spectrum disorder grew progressively throughout the fall and winter to early spring with children conceived in March having a 16 percent greater risk of later autism diagnoses, when compared with July conceptions.

The researchers said the finding suggests that environmental factors, for example, exposure to seasonal viruses like influenza, might play a role in the greater risk they found of children conceived during the winter having autism.

“The study finding was pronounced even after adjusting for factors such as maternal education, race/ethnicity, and the child’s year of conception,” said lead study author Ousseny Zerbo, a fifth-year doctoral student in the graduate group in epidemiology in the Department of Public Health Sciences in the UC Davis School of Medicine.

For the study, the researchers obtained the more than 7.2 million records for children born from January 1990 through December 2002 from the state of California Office of Vital Statistics. The researchers excluded some records because children did not survive to an age by which they typically would have been diagnosed with autism.

Other records were excluded because they were incomplete. For example, records that did not include adequate information from which to calculate the month of conception were excluded. The month of conception was calculated as the last date mothers reported having a menstrual period plus two weeks.

The total number of records finally included in the study was approximately 6.6 million, or 91 percent of all births recorded during the study period. The children were followed until their sixth birthdays to determine whether they would develop autism.

The researchers identified which children were diagnosed with autism by matching birth records with those of children receiving services from the state Department of Developmental Services (DDS). Approximately 19,000 cases of autism were identified with autism defined as “full syndrome” autism in the DDS records.

The study found that the overall risk of having a child with autism increased from month to month during the winter through the month of March. For the study, winter was considered the months of December, January and February. Each month was compared with July with an 8 percent higher incidence in December, increasing to 16 percent higher in March.

Earlier studies’ findings about autism risk and month of conception or birth have had varied results. Some, such as ones conducted in Israel, Sweden, and Denmark, have found an increased risk of autism for children born in March. Studies conducted in Canada, Japan, the United States, and the United Kingdom identified an increased risk of autism for children born in the spring. However, these studies were far smaller, most having a few hundred cases of autism, when compared with the large number in California.

“Studies of seasonal variations can provide clues about some of the underlying causes of autism. Based on this study, it may be fruitful to pursue exposures that show similar seasonal patterns, such as infections and mild nutritional deficiencies,” said Irva Hertz-Picciotto, chief of the division of environmental and occupational health in the Department of Public Health Sciences in the UC Davis School of Medicine.

“However, it might be that conception is not the time of susceptibility. Rather, it could for instance be an exposure in the third month of pregnancy, or the second trimester, that is harmful,” said Hertz-Picciotto, who also is a researcher affiliated with the UC Davis MIND Institute. “If so, we might need to look for exposures occurring a few months after conceptions that are at higher risk. For example, allergens that peak in the spring and early summer.”

The researchers said the study is a starting point for further inquiry. Other seasonal occurrences include potential exposures to pesticides, such as those used in the home to control insects in rainy or warm months, and those used in agricultural applications.

Other study authors include Ana-Maria Iosif, Lora Delwiche and Cheryl Walker of the Department of Public Health Sciences in the UC Davis School of Medicine.

Material adapted from UC Davis Health System.